ES2604943T3 - Ghrelin receptor macrocyclic modulators and procedures for their use - Google Patents
Ghrelin receptor macrocyclic modulators and procedures for their use Download PDFInfo
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- ES2604943T3 ES2604943T3 ES08799889.4T ES08799889T ES2604943T3 ES 2604943 T3 ES2604943 T3 ES 2604943T3 ES 08799889 T ES08799889 T ES 08799889T ES 2604943 T3 ES2604943 T3 ES 2604943T3
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Abstract
Un compuesto que tiene una de las siguientes estructuras:**Fórmula** o una sal farmacéuticamente aceptable del mismo.A compound having one of the following structures: ** Formula ** or a pharmaceutically acceptable salt thereof.
Description
5 5
15 fifteen
25 25
35 35
45 Four. Five
55 55
Las solicitudes de patente internacional WO 2006/009645 y WO 2006/009674 describen el uso de compuestos macrocíclicos como moduladores de la grelina para su uso en el tratamiento de trastornos GI. Se ha informado de la actividad de uno de estos compuestos en un modelo de rata de POI (Venkova, K.; Fraser, G.; Hoveyda, H.R.; Greenwood-Van Meerveld, B. Dig. Dis. Sci. 2007, 52, 2241-2248). Estos compuestos macrocíclicos son estructuralmente distintos de otros compuestos que se ha encontrado que interaccionan en el receptor de la grelina como agonistas. Por ejemplo, se ha dedicado trabajo significativo al desarrollo de GHS potentes y selectivos con varios derivados de molécula pequeña que ahora se conocen como se ha resumido recientemente (Carpino, P. Exp. Opin. Ther. Patents 2002, 12, 1599-1618). GHS específicos se describen a continuación: publicaciones de solicitud de patente internacional N.º WO 89/07110; WO 89/07111; WO 92/07578; WO 93/04081; WO 94/11012; WO 94/13696; WO 94/19367; WO 95/11029; WO 95/13069; WO 95/14666; WO 95/17422; WO 95/17423; WO 95/34311; WO 96/02530; WO 96/15148; WO 96/22996; WO 96/22997; WO 96/24580; WO 96/24587; WO 96/32943; WO 96/33189; WO 96/35713; WO 96/38471; WO 97/00894; WO 97/06803; WO 97/07117; WO 97/09060; WO 97/11697; WO 97/15191; WO 97/15573; WO 97/21730; WO 97/22004; WO 97/22367; WO 97/22620; WO 97/23508; WO 97/24369; WO 97/34604; WO 97/36873; WO 97/38709; WO 97/40023; WO 97/40071; WO 97/41878; WO 97/41879; WO 97/43278; WO 97/44042; WO 97/46252; WO 98/03473; WO 98/10653; WO 98/18815; WO 98/22124; WO 98/46569; WO 98/51687; WO 98/58947; WO 98/58948; WO 98/58949; WO 98/58950; WO 99/08697; WO 99/08699; WO 99/09991; WO 99/36431; WO 99/39730; WO 99/45029; WO 99/58501; WO 99/64456; WO 99/65486,WO 99/65488; WO 00/01726; WO 00/10975; WO 00/48623; WO 00/54729; WO 01/47558; WO 01/92292; WO 01/96300; WO 01/97831; WO 2004/021984; WO 2005/039625; WO 2005/046682; WO 2005/070884; WO 2006/044359; patente de EE.UU. No. 3.239.345; patente de EE.UU. N.º 4.036.979; patente de EE.UU. N.º 4.411.890; patente de EE.UU. N.º 5.492.916; patente de EE.UU. No. 5.494.919; patente de EE.UU. N.º 5.559.128; patente de EE.UU. N.º 5.663.171; patente de EE.UU. N.º 5.721.250; patente de EE.UU. N.º 5.721.251; patente de EE.UU. N.º 5.723.616; patente de EE.UU. N.º 5.726.319; patente de EE.UU. N.º 5.767.124; patente de EE.UU. N.º 5.798.337; patente de EE.UU. N.º 5.830.433; patente de EE.UU. N.º 5.919.777; patente de EE.UU. N.º 6.034.216; patente de EE.UU. N.º 6.548.501; patente de EE.UU. N.º 6.559.150; patente de EE.UU. N.º 6.576.686; patente de EE.UU. N.º 6.639.076; patente de EE.UU. N.º 6.686.359; patente de EE.UU. N.º 6.828.331; patente de EE.UU. N.º 6.861.409; patente de EE.UU. N.º 6.919.315; patente de EE.UU. N.º 7.034.050 y las solicitudes de patente de EE.UU. N.º 2002/0168343; 2003/100494; 2003/130284; 2003/186844; 2005/187237; 2005/233981. International patent applications WO 2006/009645 and WO 2006/009674 describe the use of macrocyclic compounds as ghrelin modulators for use in the treatment of GI disorders. The activity of one of these compounds has been reported in a POI rat model (Venkova, K .; Fraser, G .; Hoveyda, HR; Greenwood-Van Meerveld, B. Dig. Dis. Sci. 2007, 52, 2241-2248). These macrocyclic compounds are structurally distinct from other compounds that have been found to interact in the ghrelin receptor as agonists. For example, significant work has been devoted to the development of potent and selective GHS with several small molecule derivatives that are now known as recently summarized (Carpino, P. Exp. Opin. Ther. Patents 2002, 12, 1599-1618) . Specific GHSs are described below: International Patent Application Publications No. WO 89/07110; WO 89/07111; WO 92/07578; WO 93/04081; WO 94/11012; WO 94/13696; WO 94/19367; WO 95/11029; WO 95/13069; WO 95/14666; WO 95/17422; WO 95/17423; WO 95/34311; WO 96/02530; WO 96/15148; WO 96/22996; WO 96/22997; WO 96/24580; WO 96/24587; WO 96/32943; WO 96/33189; WO 96/35713; WO 96/38471; WO 97/00894; WO 97/06803; WO 97/07117; WO 97/09060; WO 97/11697; WO 97/15191; WO 97/15573; WO 97/21730; WO 97/22004; WO 97/22367; WO 97/22620; WO 97/23508; WO 97/24369; WO 97/34604; WO 97/36873; WO 97/38709; WO 97/40023; WO 97/40071; WO 97/41878; WO 97/41879; WO 97/43278; WO 97/44042; WO 97/46252; WO 98/03473; WO 98/10653; WO 98/18815; WO 98/22124; WO 98/46569; WO 98/51687; WO 98/58947; WO 98/58948; WO 98/58949; WO 98/58950; WO 99/08697; WO 99/08699; WO 99/09991; WO 99/36431; WO 99/39730; WO 99/45029; WO 99/58501; WO 99/64456; WO 99/65486, WO 99/65488; WO 00/01726; WO 00/10975; WO 00/48623; WO 00/54729; WO 01/47558; WO 01/92292; WO 01/96300; WO 01/97831; WO 2004/021984; WO 2005/039625; WO 2005/046682; WO 2005/070884; WO 2006/044359; U.S. Patent No. 3,239,345; U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No. 5,492,916; U.S. Patent No. 5,494,919; U.S. Patent No. 5,559,128; U.S. Patent No. 5,663,171; U.S. Patent No. 5,721,250; U.S. Patent No. 5,721,251; U.S. Patent No. 5,723,616; U.S. Patent No. 5,726,319; U.S. Patent No. 5,767,124; U.S. Patent No. 5,798,337; U.S. Patent No. 5,830,433; U.S. Patent No. 5,919,777; U.S. Patent No. 6,034,216; U.S. Patent No. 6,548,501; U.S. Patent No. 6,559,150; U.S. Patent No. 6,576,686; U.S. Patent No. 6,639,076; U.S. Patent No. 6,686,359; U.S. Patent No. 6,828,331; U.S. Patent No. 6,861,409; U.S. Patent No. 6,919,315; U.S. Patent No. 7,034,050 and U.S. patent applications No. 2002/0168343; 2003/100494; 2003/130284; 2003/186844; 2005/187237; 2005/233981.
A pesar de este inmenso conjunto de trabajo, raramente se ha encontrado que los compuestos cíclicos actúen en el receptor de la grelina. Cuando tienen, la actividad de antagonista ha sido más predominante. Por ejemplo, se demostró que el compuesto de 14 aminoácidos, vapreotida, un agonista de SRIH-14 y mimético de la somatostatina, era un antagonista de la grelina (Deghenghi R, Papotti M, Ghigo E, et al. Endocrine 2001, 14, 29-33). Se ha informado de la unión y actividades de antagonistas de análogos de la cortistatina, un neuropéptido cíclico que se sabe que se une no selectivamente a receptores de la somatostatina, al receptor del secretagogo de la hormona de crecimiento (solicitud de patente internacional WO 03/004518). (Deghenghi R, Broglio F, Papotti M, et al. Endocrine 2003, 22, 13-18; Sibilia, V.; Muccioli, G.; Deghenghi, R.; Pagani, F.; DeLuca, V.; Rapetti, D.; Locatelli, V.; Netti, C. J. Neuroendocrinol. 2006, 18, 122-128). En particular, se ha avanzado uno de estos análogos, EP-01492 (cortistatina8) en estudios preclínicos para el tratamiento de la obesidad como antagonista de la grelina, aunque un estudio reciente arroja dudas sobre su eficacia (Prodam, F.; Benso, A.; Gramaglia, E. Neuropeptides 2008, 42, 89-93). Estos compuestos presentan una CI50 de 24-33 nM. Además, se han descrito estos compuestos cíclicos y sus derivados, más su uso con aglutinantes metálicos, para su capacidad para ser útiles para su uso en radiodiagnóstico o radioterapéutico en el tratamiento de tumores y acromegalia. Despite this immense set of work, it has rarely been found that cyclic compounds act on the ghrelin receptor. When they have, the antagonist activity has been more predominant. For example, it was shown that the 14 amino acid compound, vapreotide, a SRIH-14 agonist and somatostatin mimetic, was a ghrelin antagonist (Deghenghi R, Papotti M, Ghigo E, et al. Endocrine 2001, 14, 29-33). The binding and activities of cortistatin analogue antagonists, a cyclic neuropeptide known to bind non-selectively to somatostatin receptors, to the growth hormone secretagogue receptor have been reported (international patent application WO 03 / 004518). (Deghenghi R, Broglio F, Papotti M, et al. Endocrine 2003, 22, 13-18; Sibilia, V .; Muccioli, G .; Deghenghi, R .; Pagani, F .; DeLuca, V .; Rapetti, D .; Locatelli, V .; Netti, CJ Neuroendocrinol. 2006, 18, 122-128). In particular, one of these analogues, EP-01492 (cortistatin8) has been advanced in preclinical studies for the treatment of obesity as a ghrelin antagonist, although a recent study casts doubt on its efficacy (Prodam, F .; Benso, A .; Gramaglia, E. Neuropeptides 2008, 42, 89-93). These compounds have an IC50 of 24-33 nM. In addition, these cyclic compounds and their derivatives have been described, plus their use with metal binders, for their ability to be useful for use in radiodiagnosis or radiotherapy in the treatment of tumors and acromegaly.
Se han estudiado análogos cíclicos y lineales de la hormona de crecimiento 177-191 como tratamientos para la obesidad (documento WO 99/12969), con un compuesto particular, AOD9604, que se ha incorporado en la clínica para esta indicación. Un compuesto ya estudiado que es el más similar a las moléculas de la presente invención es el GHS, G-7203 (CE50 = 0,43 nM), el análogo de péptido cíclico del péptido liberador de la hormona de crecimiento, GHRP-2 (Elias, K.A.; Ingle, G.S.; Burnier, J.P.; Hammonds, G.; McDowell, R.S.; Rawson, T.E.; Somers, T.C.; Stanley, M.S.; Cronin, M.J. Endocrinol. 1995, 136, 5694-5699). Sin embargo, la simplificación de este derivado cíclico condujo a compuestos lineales todavía potentes, mientras que para los compuestos macrocíclicos descritos en el presente documento se han encontrado análogos lineales que carecen de actividad del receptor de la grelina. Linear and cyclic analogs of growth hormone 177-191 have been studied as treatments for obesity (WO 99/12969), with a particular compound, AOD9604, which has been incorporated into the clinic for this indication. A compound already studied that is the most similar to the molecules of the present invention is GHS, G-7203 (EC50 = 0.43 nM), the cyclic peptide analog of the growth hormone-releasing peptide, GHRP-2 ( Elias, KA; Ingle, GS; Burnier, JP; Hammonds, G .; McDowell, RS; Rawson, TE; Somers, TC; Stanley, MS; Cronin, MJ Endocrinol. 1995, 136, 5694-5699). However, the simplification of this cyclic derivative led to still potent linear compounds, while linear analogs that lack ghrelin receptor activity have been found for the macrocyclic compounds described herein.
Se ha mostrado que los compuestos macrocíclicos descritos en el presente documento poseen actividad moduladora de la grelina, y en realizaciones particulares, como agonistas. Se han descrito previamente peptidomiméticos macrocíclicos como moduladores del receptor de la grelina y resumidos sus usos para el tratamiento de una variedad de trastornos GI y metabólicos (publicaciones de solicitud de patente internacional N.º WO 2006/009645; 2006/009674; WO 2006/046977; 2006/137974; publicaciones de solicitud de patente de EE.UU. N.º 2006/025566; 2007/0021331; solicitud de patente de EE.UU. N.º 11/774.185). Uno de estos compuestos se ha incorporado en la clínica (Lasseter, K.C.; Shaughnessy, L.; Cummings, D.; et al. J. Clin. Pharmacol. 2008, 48, 193202). The macrocyclic compounds described herein have been shown to possess ghrelin modulating activity, and in particular embodiments, as agonists. Macrocyclic peptidomimetics have been previously described as ghrelin receptor modulators and their uses summarized for the treatment of a variety of GI and metabolic disorders (International Patent Application Publications No. WO 2006/009645; 2006/009674; WO 2006 / 046977; 2006/137974; U.S. Patent Application Publications No. 2006/025566; 2007/0021331; U.S. Patent Application No. 11 / 774,185). One of these compounds has been incorporated into the clinic (Lasseter, K.C .; Shaughnessy, L .; Cummings, D .; et al. J. Clin. Pharmacol. 2008, 48, 193202).
Aunque la potencia de unión y la afinidad por la diana son factores en el descubrimiento y el desarrollo de fármacos, también son importantes para el desarrollo de agentes farmacéuticos viables la optimización de parámetros farmacocinéticos (PK) y farmacodinámicos (PD). Un área de atención para investigación en la industria farmacéutica ha sido entender mejor los factores subyacentes que determinan la idoneidad de moléculas de este modo, frecuentemente llamado coloquialmente su "similitud a fármaco" (Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Although binding potency and affinity for the target are factors in drug discovery and development, optimization of pharmacokinetic (PK) and pharmacodynamic (PD) parameters is also important for the development of viable pharmaceutical agents. One area of attention for research in the pharmaceutical industry has been to better understand the underlying factors that determine the suitability of molecules in this way, often colloquially called their "drug similarity" (Lipinski, C.A .; Lombardo, F .; Dominy, B.W .;
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Feeney, P.J. Adv. Drug Delivery Rev. 1997, 23, 3-25; Muegge, I. Med. Res. Rev. 2003, 23, 302-321; Veber, D.F.; Johnson, S.R.; Cheng, H.-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. J. Med. Chem. 2002, 45, 2615-2623). Por ejemplo, el peso molecular, log P, permeabilidad de la membrana, el número de donantes y aceptores de enlaces de hidrógeno, área superficial polar total (TPSA) y el número de enlaces giratorios se han correlacionado todos con compuestos que han sido satisfactorios en el desarrollo de fármacos. Adicionalmente, se emplean mediciones experimentales de unión a proteínas del plasma, interacción con enzimas citocromo P450, y parámetros farmacocinéticos en la industria farmacéutica para seleccionar y fomentar nuevos candidatos a fármaco. Feeney, P.J. Adv. Drug Delivery Rev. 1997, 23, 3-25; Muegge, I. Med. Res. Rev. 2003, 23, 302-321; Veber, D.F .; Johnson, S.R .; Cheng, H.-Y .; Smith, B.R .; Ward, K.W .; Kopple, K.D. J. Med. Chem. 2002, 45, 2615-2623). For example, the molecular weight, log P, membrane permeability, the number of hydrogen bond donors and acceptors, total polar surface area (TPSA) and the number of rotating bonds have all been correlated with compounds that have been satisfactory in Drug development Additionally, experimental measurements of plasma protein binding, interaction with cytochrome P450 enzymes, and pharmacokinetic parameters in the pharmaceutical industry are used to select and promote new drug candidates.
Sin embargo, estos parámetros no se han explorado o informado ampliamente en la clase estructural macrocíclica. Esta falta de información crea retos en el desarrollo de fármacos para tales moléculas. Se ha encontrado que los compuestos macrocíclicos descritos en el presente documento poseen características farmacológicas deseables, mientras que mantienen afinidad de unión y selectividad suficientes por el receptor de la grelina, como se ilustra en los ejemplos presentados en el presente documento. Estas características combinadas hacen que los compuestos macrocíclicos descritos en el presente documento generalmente sean más adecuados que los macrociclos previamente informados para desarrollo como agentes farmacéuticos, particularmente para su uso como agentes administrados por vía oral o para usos crónicos. However, these parameters have not been extensively explored or reported in the macrocyclic structural class. This lack of information creates challenges in the development of drugs for such molecules. It has been found that the macrocyclic compounds described herein possess desirable pharmacological characteristics, while maintaining sufficient binding affinity and selectivity for the ghrelin receptor, as illustrated in the examples presented herein. These combined characteristics make the macrocyclic compounds described herein generally more suitable than the macrocycles previously reported for development as pharmaceutical agents, particularly for use as orally administered agents or for chronic uses.
Sumario de la invención Summary of the invention
La presente invención proporciona novedosos compuestos macrocíclicos conformacionalmente definidos. Estos compuestos pueden servir de moduladores, en particular agonistas, del receptor de la grelina (secretagogo de la hormona de crecimiento) (GHS-R1a). The present invention provides novel conformationally defined macrocyclic compounds. These compounds can serve as modulators, in particular agonists, of the ghrelin receptor (growth hormone secretagogue) (GHS-R1a).
Según un primer aspecto de la presente invención, la presente invención se refiere a un compuesto que tiene una de las siguientes estructuras: According to a first aspect of the present invention, the present invention relates to a compound having one of the following structures:
y Y
o una sal farmacéuticamente aceptable del mismo. or a pharmaceutically acceptable salt thereof.
Un segundo aspecto de la invención proporciona un compuesto según el primer aspecto de la invención para su uso en terapia. A second aspect of the invention provides a compound according to the first aspect of the invention for use in therapy.
Un tercer aspecto de la presente invención proporciona además composiciones farmacéuticas que incluyen un compuesto del primer aspecto de la invención y un vehículo, excipiente o diluyente farmacéuticamente aceptable. En algunas realizaciones, las composiciones farmacéuticas incluyen un agonista del receptor de la grelina y al menos uno de un agonista del receptor de GLP-1, un agonista del receptor de amilina, un agonista del receptor del péptido YY (PYY) y un inhibidor del proteasoma junto con un vehículo, excipiente o diluyente farmacéuticamente aceptable. A third aspect of the present invention further provides pharmaceutical compositions that include a compound of the first aspect of the invention and a pharmaceutically acceptable carrier, excipient or diluent. In some embodiments, the pharmaceutical compositions include a ghrelin receptor agonist and at least one of a GLP-1 receptor agonist, an amylin receptor agonist, a YY peptide receptor agonist (PYY) and an inhibitor of the proteasome together with a pharmaceutically acceptable carrier, excipient or diluent.
Según dichas realizaciones, el agonista del receptor de la grelina puede seleccionarse de grelina, hexarelina, GHRP1, GHRP-2, GHRP-6, ipamorelina, tesamorelina, MK-0677, NN703, capromorelina, G7039, G7134, G7203, G7502, SM-130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-260323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187 y NNC-26-1291. According to said embodiments, the ghrelin receptor agonist can be selected from ghrelin, hexarelin, GHRP1, GHRP-2, GHRP-6, ipamorelin, tesamorelin, MK-0677, NN703, capromorelin, G7039, G7134, G7203, G7502, SM- 130686, BMS-604992, RC-1141, RC-1239, RC-1291, EX-1314, GTP-200, SUN 11031, L-692429, L-692587, L739943, L-163255, L-163540, L-163833 , L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-260323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136 , NNC-26-1137, NNC-26-1187 and NNC-26-1291.
Además, el agonista del receptor de GLP-1 puede seleccionarse de GLP-1, GLP-1 (7-36) amida, exenatida (exendina-4), liraglutida (NN2211), gilatida, albiglutida (GSK-716155, albugon), GLP1-I.N.T., AC2592, AC2993 LAR, ARI-2255, ARI-2651, BRX-0585 (GLP-1-Tf), CJC-1131, PC-DAC™:Exendina-4, CS-872, AVE-0010 (ZP-10), BIM51077 (R-1583), BIM-51182, ITM-077, SUN E7001, TH-0318, TH-0396, TTP-854, LY-315902 y LY-307161; el agonista del receptor de amilina puede seleccionarse de amilina, pramlintida, MBP-0250 o PX811016; el agonista del receptor del péptido YY puede seleccionarse de péptido YY o péptido YY 3-36 (AC-162352); y el inhibidor del proteasoma está seleccionado de bortezomib, carfilzomib (PR-171), MLN-273, MLN-519 (LDP-519), NPI-0052, (salinosporamida A), MG-132, MG-162, PR39 o CEP-18770. In addition, the GLP-1 receptor agonist can be selected from GLP-1, GLP-1 (7-36) amide, exenatide (exendin-4), liraglutide (NN2211), gilatide, albiglutide (GSK-716155, albugon), GLP1-INT, AC2592, AC2993 LAR, ARI-2255, ARI-2651, BRX-0585 (GLP-1-Tf), CJC-1131, PC-DAC ™: Exendina-4, CS-872, AVE-0010 (ZP -10), BIM51077 (R-1583), BIM-51182, ITM-077, SUN E7001, TH-0318, TH-0396, TTP-854, LY-315902 and LY-307161; the amylin receptor agonist can be selected from amylin, pramlintide, MBP-0250 or PX811016; the YY peptide receptor agonist can be selected from YY peptide or YY 3-36 peptide (AC-162352); and the proteasome inhibitor is selected from bortezomib, carfilzomib (PR-171), MLN-273, MLN-519 (LDP-519), NPI-0052, (salinosporamide A), MG-132, MG-162, PR39 or CEP -18770.
Visto desde un cuarto aspecto, la invención proporciona un compuesto del primer aspecto, para su uso en un procedimiento de tratamiento o prevención de un trastorno gastrointestinal, un trastorno metabólico o endocrino, un Viewed from a fourth aspect, the invention provides a compound of the first aspect, for use in a method of treatment or prevention of a gastrointestinal disorder, a metabolic or endocrine disorder, a
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El término "carboxialquilo" se refiere al grupo -CO2Rk, en el que Rk es alquilo, cicloalquilo o heterocíclico. The term "carboxyalkyl" refers to the group -CO2Rk, in which Rk is alkyl, cycloalkyl or heterocyclic.
El término "carboxiarilo" se refiere al grupo -CO2Rm, en el que Rm es arilo o heteroarilo. The term "carboxyaryl" refers to the group -CO2Rm, in which Rm is aryl or heteroaryl.
El término "ciano" se refiere al grupo -CN. The term "cyano" refers to the group -CN.
El término "formilo" se refiere al grupo -C(=O)H, también indicado -CHO. The term "formyl" refers to the group -C (= O) H, also indicated -CHO.
El término "halo", "halógeno" o "haluro" se refiere a fluoro, flúor o fluoruro, cloro o cloruro, bromo o bromuro, y yodo o yoduro, respectivamente. The term "halo", "halogen" or "halide" refers to fluorine, fluorine or fluoride, chlorine or chloride, bromine or bromide, and iodine or iodide, respectively.
El término "oxo" se refiere al grupo bivalente =O, que está sustituido en lugar de dos átomos de hidrógeno sobre el mismo carbono para formar un grupo carbonilo. The term "oxo" refers to the bivalent group = O, which is substituted instead of two hydrogen atoms on the same carbon to form a carbonyl group.
El término "mercapto" se refiere al grupo -SRn en el que Rn es hidrógeno, alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo. The term "mercapto" refers to the group -SRn in which Rn is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl.
El término "nitro" se refiere al grupo -NO2. The term "nitro" refers to the group -NO2.
El término "trifluorometilo" se refiere al grupo -CF3. The term "trifluoromethyl" refers to the group -CF3.
El término "sulfinilo" se refiere al grupo -S(=O)Rp en el que Rp es alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo. The term "sulfinyl" refers to the group -S (= O) Rp in which Rp is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl.
El término "sulfonilo" se refiere al grupo -S(=O)2-Rq1 en el que Rq1 es alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo. The term "sulfonyl" refers to the group -S (= O) 2-Rq1 in which Rq1 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl.
El término "aminosulfonilo" se refiere al grupo -NRq2-S(=O)2-Rq3 en el que Rq2 es hidrógeno, alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo; y Rq3 es alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo. The term "aminosulfonyl" refers to the group -NRq2-S (= O) 2-Rq3 in which Rq2 is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; and Rq3 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl.
El término "sulfonamido" se refiere al grupo -S(=O)2-NRrRs en el que Rr y Rs están seleccionados independientemente del grupo que consiste en hidrógeno, alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo. Alternativamente, Rr y Rs juntos forman un anillo heterocíclico de 3 a 8 miembros, opcionalmente sustituido con alquilo sin sustituir, cicloalquilo sin sustituir, heterocíclico sin sustituir, arilo sin sustituir, heteroarilo sin sustituir, hidroxi, alcoxi, ariloxi, acilo, amino, amido, carboxi, carboxialquilo, carboxiarilo, mercapto, sulfinilo, sulfonilo, sulfonamido, amidino, carbamoílo, guanidino o ureido, y que opcionalmente contiene uno a tres heteroátomos adicionales seleccionados de O, S o N. The term "sulfonamido" refers to the group -S (= O) 2-NRrRs in which Rr and Rs are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl. Alternatively, Rr and Rs together form a 3- to 8-membered heterocyclic ring, optionally substituted with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amido , carboxy, carboxy alkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, and which optionally contains one to three additional heteroatoms selected from O, S or N.
El término "carbamoílo" se refiere a un grupo de fórmula -N(Rt)-C(=O)-ORu en la que Rt está seleccionado de hidrógeno, alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo; y Ru está seleccionado de alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo. The term "carbamoyl" refers to a group of the formula -N (Rt) -C (= O) -ORu in which Rt is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; and Ru is selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl.
El término "guanidino" se refiere a un grupo de fórmula -N(Rv)-C(=NRw)-NRxRy en la que Rv, Rw, Rx y Ry están seleccionados independientemente de hidrógeno, alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo. Alternativamente, Rx y Ry juntos forman un anillo heterocíclico de 3 a 8 miembros, opcionalmente sustituido con alquilo sin sustituir, cicloalquilo sin sustituir, heterocíclico sin sustituir, arilo sin sustituir, heteroarilo sin sustituir, hidroxi, alcoxi, ariloxi, acilo, amino, amido, carboxi, carboxialquilo, carboxiarilo, mercapto, sulfinilo, sulfonilo, sulfonamido, amidino, carbamoílo, guanidino o ureido, y que opcionalmente contiene uno a tres heteroátomos adicionales seleccionados de O, S o N. The term "guanidino" refers to a group of the formula -N (Rv) -C (= NRw) -NRxRy in which Rv, Rw, Rx and Ry are independently selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl . Alternatively, Rx and Ry together form a 3- to 8-membered heterocyclic ring, optionally substituted with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amido , carboxy, carboxy alkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, and which optionally contains one to three additional heteroatoms selected from O, S or N.
El término "ureido" se refiere a un grupo de fórmula -N(Rz)-C(=O)-NRaaRbb en la que Rz, Raa y Rbb están seleccionados independientemente de hidrógeno, alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo. Alternativamente, Raa y Rbb juntos forman un anillo heterocíclico de 3 a 8 miembros, opcionalmente sustituido con alquilo sin sustituir, cicloalquilo sin sustituir, heterocíclico sin sustituir, arilo sin sustituir, heteroarilo sin sustituir, hidroxi, alcoxi, ariloxi, acilo, amino, amido, carboxi, carboxialquilo, carboxiarilo, mercapto, sulfinilo, sulfonilo, sulfonamido, amidino, carbamoílo, guanidino o ureido, y que opcionalmente contiene uno a tres heteroátomos adicionales seleccionados de O, S o N. The term "ureido" refers to a group of the formula -N (Rz) -C (= O) -NRaaRbb in which Rz, Raa and Rbb are independently selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl. Alternatively, Raa and Rbb together form a 3- to 8-membered heterocyclic ring, optionally substituted with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amido , carboxy, carboxy alkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, and which optionally contains one to three additional heteroatoms selected from O, S or N.
El término "opcionalmente sustituido" pretende indicar expresamente que el grupo especificado está sin sustituir o sustituido con uno o más sustituyentes adecuados, a menos que los sustituyentes opcionales se especifiquen expresamente, en cuyo caso el término indica que el grupo está sin sustituir o sustituido con los sustituyentes especificados. Como se ha definido anteriormente, diversos grupos pueden estar sin sustituir o sustituidos (es decir, están opcionalmente sustituidos), a menos que se indique lo contrario en el presente documento (por ejemplo, indicando que el grupo especificado está sin sustituir). The term "optionally substituted" is expressly intended to indicate that the specified group is unsubstituted or substituted with one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with The specified substituents. As defined above, various groups may be unsubstituted or substituted (ie, they are optionally substituted), unless otherwise indicated herein (for example, indicating that the specified group is unsubstituted).
El término "sustituido", cuando se usa con los términos alquilo, cicloalquilo, heterocíclico, arilo y heteroarilo, se refiere a un grupo alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo que tiene uno o más de los átomos de hidrógeno del grupo sustituidos con sustituyentes independientemente seleccionados de alquilo sin sustituir, cicloalquilo sin sustituir, heterocíclico sin sustituir, arilo sin sustituir, heteroarilo sin sustituir, hidroxi, alcoxi, ariloxi, The term "substituted", when used with the terms alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, refers to an alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group having one or more of the hydrogen atoms of the group substituted with substituents independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy,
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receptor y liberación o secreción de hormona. Procesos o mecanismos químicos a modo de ejemplo afectados por un modulador incluyen, pero no se limitan a, catálisis e hidrólisis. receptor and hormone release or secretion. Exemplary chemical processes or mechanisms affected by a modulator include, but are not limited to, catalysis and hydrolysis.
El término "variante" cuando se aplica a un receptor pretende incluir dímeros, trímeros, tetrámeros, pentámeros y otros complejos biológicos que contienen múltiples componentes. Estos componentes pueden ser iguales o diferentes. The term "variant" when applied to a receptor is intended to include dimers, trimers, tetramers, pentamers and other biological complexes that contain multiple components. These components may be the same or different.
El término "péptido" se refiere a un compuesto químico comprendido de dos o más aminoácidos covalentemente unidos juntos. The term "peptide" refers to a chemical compound comprised of two or more amino acids covalently linked together.
El término "peptidomimético" se refiere a un compuesto químico diseñado para imitar un péptido, pero que contiene diferencias estructurales mediante la adición o sustitución de uno de más grupos funcionales del péptido con el fin de modular su actividad u otras propiedades, tales como la solubilidad, estabilidad metabólica, biodisponibilidad oral, lipofilia, permeabilidad, etc. Esto puede incluir la sustitución del enlace peptídico, modificaciones de la cadena lateral, truncaciones, adiciones de grupos funcionales, etc. Cuando la estructura química no se deriva del péptido, pero imita su actividad, se denomina frecuentemente un "peptidomimético no peptídico". The term "peptidomimetic" refers to a chemical compound designed to mimic a peptide, but which contains structural differences by adding or replacing one of more functional groups of the peptide in order to modulate its activity or other properties, such as solubility. , metabolic stability, oral bioavailability, lipophilicity, permeability, etc. This may include the replacement of the peptide bond, side chain modifications, truncations, additions of functional groups, etc. When the chemical structure is not derived from the peptide, but mimics its activity, it is often referred to as a "non-peptide peptidomimetic."
El término "enlace peptídico" se refiere a la funcionalidad amida [-C(=O)-NH-] con la que aminoácidos individuales normalmente se unen covalentemente entre sí en un péptido. The term "peptide bond" refers to the amide functionality [-C (= O) -NH-] with which individual amino acids normally covalently bind to each other in a peptide.
El término "grupo protector" se refiere a cualquier compuesto químico que pueda usarse para prevenir que un grupo funcional potencialmente reactivo, tal como una amina, un hidroxilo o un carboxilo, sobre una molécula experimente una reacción química mientras que el cambio químico se produce en cualquier parte en la molécula. Varios de tales grupos protectores son conocidos para aquellos expertos en la materia, y pueden encontrarse ejemplos en "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter G. Wuts, editors, John Wiley & Sons, New York, 3ª edición, 1999 [ISBN 0471160199]. Ejemplos de grupos protectores de amino incluyen, pero no se limitan a, ftalimido, tricloroacetilo, benciloxicarbonilo, terc-butoxicarbonilo y adamantiloxicarbonilo. En algunas realizaciones, los grupos protectores de amino son grupos protectores de amino del carbamato, que se definen como un grupo protector de amino que cuando se une a un grupo amino forma un carbamato. En otras realizaciones, grupos protectores del carbamato de amino son aliloxicarbonilo (Alloc), benciloxicarbonilo (Cbz), 9-fluorenilmetoxicarbonilo (Fmoc), terc-butoxicarbonilo (Boc) y α,α-dimetil-3,5-dimetoxibenciloxicarbonilo (Ddz). Para una discusión reciente de grupos protectores de nitrógeno más nuevos: Theodoridis, G. Tetrahedron 2000, 56, 2339-2358. Ejemplos de grupos protectores de hidroxilo incluyen, pero no se limitan a, acetilo, terc-butildimetilsililo (TBDMS), tritilo (Trt), terc-butilo y tetrahidropiranilo (THP). Ejemplos de grupos protectores de carboxilo incluyen, pero no se limitan a, éster metílico, éster terc-butílico, éster bencílico, éster trimetilsililetílico y éster 2,2,2-tricloroetílico. The term "protecting group" refers to any chemical compound that can be used to prevent a potentially reactive functional group, such as an amine, a hydroxyl or a carboxyl, on a molecule from undergoing a chemical reaction while chemical change occurs in Any part in the molecule. Several such protecting groups are known to those skilled in the art, and examples can be found in "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter G. Wuts, editors, John Wiley & Sons, New York, 3rd edition, 1999 [ISBN 0471160199]. Examples of amino protecting groups include, but are not limited to, phthalimido, trichloroacetyl, benzyloxycarbonyl, tert-butoxycarbonyl and adamantyloxycarbonyl. In some embodiments, the amino protecting groups are carbamate amino protecting groups, which are defined as an amino protecting group that when it binds to an amino group forms a carbamate. In other embodiments, amino carbamate protecting groups are allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc) and α, α-dimethyl-3,5-dimethoxybenzyloxycarbonyl (Ddz). For a recent discussion of newer nitrogen protecting groups: Theodoridis, G. Tetrahedron 2000, 56, 2339-2358. Examples of hydroxyl protecting groups include, but are not limited to, acetyl, tert-butyldimethylsilyl (TBDMS), trityl (Trt), tert-butyl and tetrahydropyranyl (THP). Examples of carboxyl protecting groups include, but are not limited to, methyl ester, tert-butyl ester, benzyl ester, trimethylsilylethyl ester and 2,2,2-trichlorethyl ester.
El término "química en fase sólida" se refiere a la realización de reacciones químicas donde un componente de la reacción se une covalentemente a un material polimérico (soporte sólido como se define a continuación). Los procedimientos de reacción para realizar la química sobre fase sólida han llegado a ser más ampliamente conocidos y establecidos fuera de los campos tradicionales de la química de los péptidos y los oligonucleótidos. The term "solid phase chemistry" refers to the performance of chemical reactions where a component of the reaction covalently binds to a polymeric material (solid support as defined below). Reaction procedures for performing solid phase chemistry have become more widely known and established outside the traditional fields of peptide and oligonucleotide chemistry.
El término "soporte sólido", "fase sólida" o "resina" se refiere a una matriz polimérica mecánica y químicamente estable utilizada para realizar la química en fase sólida. Esto se indica por "Resina", "P-" o el siguiente símbolo: The term "solid support", "solid phase" or "resin" refers to a mechanically and chemically stable polymer matrix used to perform solid phase chemistry. This is indicated by "Resin", "P-" or the following symbol:
Ejemplos de materiales de polímero apropiados incluyen, pero no se limitan a, poliestireno, polietileno, polietilenglicol, polietilenglicol injertado o covalentemente unido a poliestireno (también llamado PEG-poliestireno, TentaGel™, Rapp, W.; Zhang, L.; Bayer, E. en Innovations and Persepctives in Solid Phase Synthesis. Peptides, Polypeptides and Oligonucleotides; Epton, R., Ed.; SPCC Ltd.: Birmingham, RU; p 205), poliacrilato (CLEAR™), poliacrilamida, poliuretano, PEGA [co-polímero de polietilenglicol-poli(N,N-dimetilacrilamida), Meldal, M. Tetrahedron Lett. 1992, 33, 3077-3080], celulosa, etc. Estos materiales pueden opcionalmente contener agentes químicos adicionales para formar enlaces reticulados para estabilizar mecánicamente la estructura, por ejemplo, poliestireno reticulado con divinilbenceno (DVB, normalmente 0,1-5 %, preferentemente 0,5-2 %). Este soporte sólido puede incluir como ejemplos no limitantes aminometilpoliestireno, hidroximetilpoliestireno, benzhidrilamina poliestireno (BHA), metilbenzhidrilamina (MBHA) poliestireno, y otros esqueletos poliméricos que contienen grupos funcionales químicos libres, lo más normalmente, -NH2 o -OH, para derivatización o reacción adicional. El término también pretende incluir "Ultra-resinas" con una alta proporción ("carga") de estos grupos funcionales tales como aquellas preparadas a partir de polietileniminas y moléculas de reticulación (Barth, M.; Rademann, J. J. Comb. Chem. 2004, 6, 340-349). Al finalizar la síntesis, las resinas normalmente se desechan, aunque se ha mostrado que son capaces de ser reutilizadas, tal como en Frechet, J.M.J.; Haque, K.E. Tetrahedron Lett. 1975, 16, 3055. Examples of suitable polymer materials include, but are not limited to, polystyrene, polyethylene, polyethylene glycol, grafted polyethylene glycol or covalently bonded to polystyrene (also called PEG-polystyrene, TentaGel ™, Rapp, W .; Zhang, L .; Bayer, E in Innovations and Persepctives in Solid Phase Synthesis, Peptides, Polypeptides and Oligonucleotides; Epton, R., Ed .; SPCC Ltd .: Birmingham, RU; p 205), polyacrylate (CLEAR ™), polyacrylamide, polyurethane, PEGA [co- polyethylene glycol-poly (N, N-dimethylacrylamide) polymer, Meldal, M. Tetrahedron Lett. 1992, 33, 3077-3080], cellulose, etc. These materials may optionally contain additional chemical agents to form crosslinked bonds to mechanically stabilize the structure, for example, polystyrene crosslinked with divinylbenzene (DVB, typically 0.1-5%, preferably 0.5-2%). This solid support may include as non-limiting examples aminomethyl polystyrene, hydroxymethyl polystyrene, benzhydrylamine polystyrene (BHA), methylbenzhydrylamine (MBHA) polystyrene, and other polymeric skeletons containing free chemical functional groups, most commonly, -NH2 or -OH, for derivatization or reaction additional. The term is also intended to include "Ultra-resins" with a high proportion ("load") of these functional groups such as those prepared from polyethyleneimines and cross-linking molecules (Barth, M .; Rademann, JJ Comb. Chem. 2004, 6, 340-349). At the end of the synthesis, the resins are normally discarded, although it has been shown that they are capable of being reused, as in Frechet, J.M.J .; Haque, K.E. Tetrahedron Lett. 1975, 16, 3055.
En general, los materiales usados como resinas son polímeros insolubles, pero ciertos polímeros tienen solubilidad diferencial dependiendo del disolvente y también pueden emplearse para química en fase sólida. Por ejemplo, puede utilizarse polietilenglicol de este modo, ya que es soluble en muchos disolventes orgánicos en los que pueden realizarse reacciones químicas, pero es insoluble en otros, tales como éter dietílico. Por lo tanto, pueden realizarse In general, the materials used as resins are insoluble polymers, but certain polymers have differential solubility depending on the solvent and can also be used for solid phase chemistry. For example, polyethylene glycol can be used in this way, since it is soluble in many organic solvents in which chemical reactions can be performed, but is insoluble in others, such as diethyl ether. Therefore, they can be done
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reacciones homogéneamente en solución, luego precipitarse el producto sobre el polímero mediante la adición de éter dietílico y procesarse como un sólido. Esto se ha llamado química de "fase líquida". reactions homogeneously in solution, then the product is precipitated on the polymer by the addition of diethyl ether and processed as a solid. This has been called "liquid phase" chemistry.
El término "conector", cuando se usa en referencia a la química de la fase sólida, se refiere a un grupo químico que está unido covalentemente a un soporte sólido y está unido entre el soporte y el sustrato normalmente con el fin de permitir la liberación (escisión) del sustrato del soporte sólido. Sin embargo, también puede usarse para conferir estabilidad al enlace al soporte sólido o simplemente como elemento espaciador. Muchos soportes sólidos están comercialmente disponibles con conectores ya unidos. The term "connector", when used in reference to solid phase chemistry, refers to a chemical group that is covalently bonded to a solid support and is bonded between the support and the substrate normally in order to allow release. (cleavage) of the solid support substrate. However, it can also be used to impart stability to the bond to the solid support or simply as a spacer element. Many solid supports are commercially available with already attached connectors.
Abreviaturas usadas para aminoácidos y la designación de péptidos siguen las reglas de la UPAC-IUB Commission of Biochemical Nomenclature in J. Biol. Chem. 1972, 247, 977-983. Este documento ha sido actualizado: Biochem. J., 1984, 219, 345-373; Eur. J. Biochem., 1984, 138, 9-37; 1985, 152, 1; Internat. J. Pept. Prot. Res., 1984, 24, a continuación p 84; J. Biol. Chem., 1985, 260, 14-42; Pure Appl. Chem., 1984, 56, 595-624; Amino Acids and Peptides, 1985, 16, 387-410; y en Biochemical Nomenclature and Related Documents, 2ª edición, Portland Press, 1992, pp 39-67. Extensiones a las reglas fueron publicadas en JCBN/NC-IUB Newsletter 1985, 1986, 1989; véase Biochemical Nomenclature and Related Documents, 2ª edición, Portland Press, 1992, pp 68-69. Abbreviations used for amino acids and peptide designation follow the rules of the UPAC-IUB Commission of Biochemical Nomenclature in J. Biol. Chem. 1972, 247, 977-983. This document has been updated: Biochem. J., 1984, 219, 345-373; Eur. J. Biochem., 1984, 138, 9-37; 1985, 152, 1; Internat. J. Pept. Prot. Res., 1984, 24, below p 84; J. Biol. Chem., 1985, 260, 14-42; Pure Appl. Chem., 1984, 56, 595-624; Amino Acids and Peptides, 1985, 16, 387-410; and in Biochemical Nomenclature and Related Documents, 2nd edition, Portland Press, 1992, pp 39-67. Extensions to the rules were published in JCBN / NC-IUB Newsletter 1985, 1986, 1989; see Biochemical Nomenclature and Related Documents, 2nd edition, Portland Press, 1992, pp 68-69.
Está previsto que el término "cantidad eficaz" o "eficaz" designe una dosis que produce un alivio de síntomas de una enfermedad o trastorno como se indica mediante pruebas clínicas y evaluación, observación del paciente, y/o similares, y/o una dosis que produce un cambio detectable en la actividad biológica o química. Los cambios detectables pueden detectarse y/o cuantificarse adicionalmente por un experto en la materia para el mecanismo o proceso relevante. Como es generalmente entendido en la materia, la dosificación variará dependiendo de las vías de administración, síntomas y peso corporal del paciente, pero también dependiendo del compuesto que se administra. The term "effective" or "effective amount" is intended to designate a dose that produces relief of symptoms of a disease or disorder as indicated by clinical tests and evaluation, patient observation, and / or the like, and / or a dose. which produces a detectable change in biological or chemical activity. The detectable changes can be detected and / or further quantified by a person skilled in the art for the relevant mechanism or process. As is generally understood in the art, the dosage will vary depending on the routes of administration, symptoms and body weight of the patient, but also depending on the compound that is administered.
La administración de dos o más compuestos "en combinación" significa que los dos compuestos se administran tan suficientemente próximos en el tiempo que la presencia de uno altera los efectos biológicos del otro. Los dos compuestos pueden administrarse simultáneamente (concurrentemente) o secuencialmente. La administración simultánea puede llevarse a cabo mezclando los compuestos antes de la administración, o administrando los compuestos en el mismo momento de tiempo, pero en diferentes sitios anatómicos o usando diferentes vías de administración. Las expresiones "administración concurrente", "administración en combinación", "administración simultánea" o "administrado simultáneamente", como se usan en el presente documento, significan que los compuestos se administran en el mismo momento de tiempo o inmediatamente uno tras otro. En el último caso, los dos compuestos se administran en momentos suficientemente próximos tal que los resultados observados sean indistinguibles de aquellos logrados cuando los compuestos se administran en el mismo momento de tiempo. The administration of two or more compounds "in combination" means that the two compounds are administered so close enough in time that the presence of one alters the biological effects of the other. The two compounds can be administered simultaneously (concurrently) or sequentially. Simultaneous administration can be carried out by mixing the compounds before administration, or by administering the compounds at the same time, but at different anatomical sites or using different routes of administration. The terms "concurrent administration", "combination administration", "simultaneous administration" or "simultaneously administered", as used herein, mean that the compounds are administered at the same time or immediately one after another. In the latter case, the two compounds are administered at sufficiently close times such that the observed results are indistinguishable from those achieved when the compounds are administered at the same time.
Además, los compuestos de la presente invención pueden administrarse en combinación con otro compuesto, tal como un agente(s) particular(es), de un modo que contemple administrar los compuestos de la presente invención antes de iniciar la terapia con el (los) agente(s) particular(es) con el fin de prevenir y/o tratar los efectos del (de los) agente(s) particular(es). In addition, the compounds of the present invention may be administered in combination with another compound, such as a particular agent (s), in a manner that contemplates administering the compounds of the present invention before initiating therapy with the (the) particular agent (s) in order to prevent and / or treat the effects of the particular agent (s).
El término "metabolito farmacéuticamente activo" pretende significar un producto farmacológicamente activo producido mediante el metabolismo en el cuerpo de un compuesto especificado. The term "pharmaceutically active metabolite" is intended to mean a pharmacologically active product produced by the metabolism in the body of a specified compound.
El término "solvato" pretende significar una forma de solvato farmacéuticamente aceptable de un compuesto especificado que retiene la eficacia biológica de tal compuesto. Ejemplos de solvatos, sin limitación, incluyen compuestos de la invención en combinación con agua, isopropanol, etanol, metanol, DMSO, acetato de etilo, ácido acético, o etanolamina. The term "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological efficacy of such a compound. Examples of solvates, without limitation, include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
1. Compuestos 1. Compounds
Los novedosos compuestos macrocíclicos descritos en el presente documento (incluyendo aquellos de la presente invención) incluyen compuestos macrocíclicos que comprenden una estructura de elemento estructural que incluye un componente conector que se somete a ciclación para formar el compuesto macrocíclico. La estructura de elemento estructural puede comprender aminoácidos (estándar y no naturales), hidroxiácidos, hidrazinoácidos, azaaminoácidos, restos especializados tales como aquellos que desempeñan una función en la introducción de sustitutos e isósteros de péptido, y un componente conector como se describe en el presente documento. The novel macrocyclic compounds described herein (including those of the present invention) include macrocyclic compounds comprising a structural element structure that includes a linker component that is cyclized to form the macrocyclic compound. The structural element structure may comprise amino acids (standard and non-natural), hydroxy acids, hydrazino acids, azaamino acids, specialized moieties such as those that play a role in the introduction of peptide substitutes and isosters, and a linker component as described herein. document.
La presente invención incluye compuestos aislados. Un compuesto aislado se refiere a un compuesto que, en algunas realizaciones, comprende al menos el 10 %, al menos el 25 %, al menos el 50 % o al menos el 70 % de los compuestos de una mezcla. En algunas realizaciones, el compuesto, sal farmacéuticamente aceptable del mismo o composición farmacéutica que contiene el compuesto presenta una unión y/o actividad de antagonista estadísticamente significativa cuando se prueba en ensayos biológicos en el receptor de la grelina humana. The present invention includes isolated compounds. An isolated compound refers to a compound that, in some embodiments, comprises at least 10%, at least 25%, at least 50% or at least 70% of the compounds in a mixture. In some embodiments, the compound, pharmaceutically acceptable salt thereof or pharmaceutical composition containing the compound exhibits a statistically significant antagonist binding and / or activity when tested in biological assays on the human ghrelin receptor.
En el caso de compuestos, sales o solvatos que son sólidos, se entiende por aquellos expertos en la materia que los compuestos inventivos, sales y solvatos pueden existir en diferentes formas cristalinas o polimórficas, todas las cuales pretenden estar dentro del alcance de la presente invención y las fórmulas especificadas. In the case of compounds, salts or solvates that are solid, it is understood by those skilled in the art that inventive compounds, salts and solvates may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention. and the specified formulas.
5 5
10 10
15 fifteen
20 twenty
25 25
30 30
35 35
40 40
45 Four. Five
50 fifty
55 55
Los compuestos desvelados en el presente documento pueden tener centros asimétricos. Los compuestos inventivos pueden existir como estereoisómeros individuales, racematos, y/o mezclas de enantiómeros y/o diaestereómeros. Todos aquellos estereoisómeros individuales, racematos, y mezclas de los mismos, pretenden estar dentro del alcance de la presente invención. En realizaciones particulares, sin embargo, los compuestos inventivos se usan en forma ópticamente pura. Los términos configuración "S" y "R", como se usan en el presente documento, son como se definen por la IUPAC 1974 Recommendations for Section E, Fundamentals of Stereochemistry (Pure Appl. Chem. 1976, 45, 13-30). The compounds disclosed herein may have asymmetric centers. The inventive compounds may exist as individual stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. All those individual stereoisomers, racemates, and mixtures thereof, are intended to be within the scope of the present invention. In particular embodiments, however, the inventive compounds are used in optically pure form. The terms "S" and "R", as used herein, are as defined by the IUPAC 1974 Recommendations for Section E, Fundamentals of Stereochemistry (Pure Appl. Chem. 1976, 45, 13-30).
A menos que se represente de otro modo para ser una orientación específica, la presente invención representa todas las formas estereoisoméricas. Los compuestos pueden prepararse como un estereoisómero individual o una mezcla de estereoisómeros. Las formas no racémicas pueden obtenerse por tanto síntesis como resolución. Los compuestos pueden resolverse, por ejemplo, en los enantiómeros componente por técnicas convencionales, por ejemplo, formación de pares diaestereoméricos mediante la formación de sal. Los compuestos también pueden resolverse uniendo covalentemente a un resto quiral. Los diaestereómeros pueden entonces resolverse por separación cromatográfica y/o separación cristalográfica. En el caso de un resto auxiliar quiral, puede entonces eliminarse. Como alternativa, los compuestos pueden resolverse mediante el uso de cromatografía quiral. También podrían usarse en ciertos casos procedimientos enzimáticos de resolución. Unless otherwise represented to be a specific orientation, the present invention represents all stereoisomeric forms. The compounds can be prepared as an individual stereoisomer or a mixture of stereoisomers. Non-racemic forms can be obtained by both synthesis and resolution. The compounds can be resolved, for example, in the component enantiomers by conventional techniques, for example, formation of diastereomeric pairs by salt formation. The compounds can also be resolved by covalently binding a chiral moiety. The diastereomers can then be resolved by chromatographic separation and / or crystallographic separation. In the case of a chiral auxiliary moiety, it can then be removed. Alternatively, the compounds can be resolved by the use of chiral chromatography. Enzymatic resolution procedures could also be used in certain cases.
Como generalmente es entendido por aquellos expertos en la materia, un compuesto "ópticamente puro" es uno que contiene solo un enantiómero individual. Como se usa en el presente documento, el término "ópticamente activo" pretende significar un compuesto que comprende al menos un exceso suficiente de un enantiómero con respecto al otro de forma que la mezcla gire el plano de la luz polarizada. Los compuestos ópticamente activos tienen la capacidad de girar el plano de la luz polarizada. El exceso de un enantiómero con respecto al otro normalmente se expresa como exceso enantiomérico (e.e.). En la descripción de un compuesto ópticamente activo, los prefijos D y L As generally understood by those skilled in the art, an "optically pure" compound is one that contains only one individual enantiomer. As used herein, the term "optically active" is intended to mean a compound comprising at least a sufficient excess of one enantiomer with respect to the other so that the mixture rotates the plane of polarized light. Optically active compounds have the ability to rotate the plane of polarized light. The excess of one enantiomer with respect to the other is usually expressed as an enantiomeric excess (e.e.). In the description of an optically active compound, the prefixes D and L
o R y S se usan para indicar la configuración absoluta de la molécula alrededor de su(s) centro(s) quiral(es). Los prefijos "d" y "l" o (+) y (-) se usan para indicar la rotación óptica del compuesto (es decir, la dirección en la que un plano de luz polarizada es girado por el compuesto ópticamente activo). El prefijo "l" o (-) indica que el compuesto es dextrógiro (es decir, gira el plano de la luz polarizada a la izquierda o en el sentido en contra de las agujas del reloj) mientras que el prefijo "d" o (+) significa que el compuesto es levógiro (es decir, gira el plano de la luz polarizada a la derecha o en el sentido de las agujas del reloj). El signo de la rotación óptica, (-) y (+), no está relacionado con la configuración absoluta de la molécula, R y S. or R and S are used to indicate the absolute configuration of the molecule around its chiral center (s). The prefixes "d" and "l" or (+) and (-) are used to indicate the optical rotation of the compound (that is, the direction in which a plane of polarized light is rotated by the optically active compound). The prefix "l" or (-) indicates that the compound is dextrogyric (that is, rotates the plane of polarized light counterclockwise or counterclockwise) while the prefix "d" or ( +) means that the compound is levógiro (that is, rotates the plane of polarized light clockwise or clockwise). The sign of the optical rotation, (-) and (+), is not related to the absolute configuration of the molecule, R and S.
Un compuesto de la invención que tiene las propiedades farmacológicas deseadas será ópticamente activo y, puede comprender al menos el 90 % (80 % de e.e.), al menos el 95 % (90 % de e.e.), al menos el 97,5 % (95 % de e.e). o al menos el 99 % (98 % de e.e). de un isómero individual. A compound of the invention having the desired pharmacological properties will be optically active and may comprise at least 90% (80% ee), at least 95% (90% ee), at least 97.5% ( 95% of ee). or at least 99% (98% of e.e). of an individual isomer.
Asimismo, muchos isómeros geométricos de dobles enlaces y similares también pueden estar presentes en los compuestos desvelados en el presente documento, y todos aquellos isómeros estables están incluidos dentro de la presente invención, a menos que se especifique de otro modo. También están incluidos en la invención tautómeros y rotámeros de los compuestos. Likewise, many geometric double bond isomers and the like can also be present in the compounds disclosed herein, and all those stable isomers are included within the present invention, unless otherwise specified. Tautomers and rotamers of the compounds are also included in the invention.
El uso de los siguiente símbolos a la derecha se refiere a la sustitución de uno o más átomos de hidrógeno del anillo indicado The use of the following symbols on the right refers to the substitution of one or more hydrogen atoms of the indicated ring
con el sustituyente R definido. with the substituent R defined.
El uso del siguiente símbolo indica un enlace sencillo o un doble enlace opcional: ----. The use of the following symbol indicates a single link or an optional double link: ----.
2. Procedimientos sintéticos 2. Synthetic procedures
Los compuestos de la presente invención pueden sintetizarse usando técnicas de síntesis en solución tradicionales The compounds of the present invention can be synthesized using traditional solution synthesis techniques
o procedimientos de química en fase sólida. En cualquiera, la construcción implica cuatro fases: primera, síntesis de las unidades estructurales que comprenden elementos de reconocimiento para el receptor diana biológico, más un resto conector, principalmente para el control y la definición de la conformación. Estas unidades estructurales se ensamblan juntas, normalmente de un modo secuencial, en una segunda fase empleando transformaciones químicas estándar. Los precursores del ensamblaje se ciclan entonces en la tercera fase para proporcionar las estructuras macrocíclicas. Finalmente, la cuarta etapa de procesamiento post-ciclación que implica la eliminación de grupos protectores y la purificación opcional proporciona los compuestos finales deseados. Procedimientos sintéticos para este tipo general de estructura macrocíclica se describen en las solicitudes de patente internacional WO 01/25257, WO 2004/111077, WO 2005/012331 y WO 2005/012332, que incluyen procedimientos de purificación descritos en los documento WO 2004/111077 y WO 2005/012331. Véanse también las solicitudes de patente de EE.UU. N.º de serie 11/149.512 y 11/149.731. or solid phase chemistry procedures. In any one, the construction involves four phases: first, synthesis of the structural units comprising recognition elements for the biological target receptor, plus a linker moiety, mainly for the control and definition of the conformation. These structural units are assembled together, usually sequentially, in a second phase using standard chemical transformations. The assembly precursors are then cycled in the third phase to provide the macrocyclic structures. Finally, the fourth stage of post-cyclization processing that involves the removal of protective groups and optional purification provides the desired final compounds. Synthetic procedures for this general type of macrocyclic structure are described in international patent applications WO 01/25257, WO 2004/111077, WO 2005/012331 and WO 2005/012332, which include purification procedures described in WO 2004/111077 and WO 2005/012331. See also US patent applications. Serial No. 11 / 149,512 and 11 / 149,731.
En algunas realizaciones de la presente invención, los compuestos macrocíclicos pueden sintetizarse usando In some embodiments of the present invention, macrocyclic compounds can be synthesized using
Esquema 2: Metodologías de ciclación alternativas Scheme 2: Alternative Cycling Methodologies
La siguiente tabla proporciona información sobre las unidades estructurales usadas para la síntesis de los compuestos descritos en el presente documento, incluyendo los compuestos de la presente invención, usando los procedimientos convencionales. Éstas son directamente aplicables a la síntesis en fase sólida. Para las síntesis en fase de solución, se emplean estrategias de protección modificadas de las ilustradas normalmente para permitir el uso de un enfoque convergente. Detalles sintéticos adicionales para la construcción de la fase de solución de compuestos macrocíclicos se presentan en los ejemplos. The following table provides information on the structural units used for the synthesis of the compounds described herein, including the compounds of the present invention, using conventional procedures. These are directly applicable to solid phase synthesis. For solution phase syntheses, modified protection strategies of those normally illustrated are used to allow the use of a convergent approach. Additional synthetic details for the construction of the solution phase of macrocyclic compounds are presented in the examples.
Síntesis de compuestos de la invención (Compuestos 801, 807 y 825) y compuestos no de la invención Synthesis of compounds of the invention (Compounds 801, 807 and 825) and compounds not of the invention
- Compuesto Compound
- AA1 AA2 AA3 Conector AA1 AA2 AA3 Connector
- 801 801
- Bts-Chg Boc-(D)NMeAla Boc-(D)Leu Boc-T100a Bts-chg Boc- (D) NMeAla Boc- (D) Leu Boc-T100a
- 802 802
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T100a Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T100a
- 803 803
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T100a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T100a
- 807 807
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T101c Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T101c
- 808 808
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T101c Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T101c
- 809 809
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T69 Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T69
- 810 810
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T69 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T69
- 813 813
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T86 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T86
- 816 816
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T85 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T85
- 818 818
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T85 Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T85
- 819 819
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T124a Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T124a
- 820 820
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T124a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T124a
- 822 822
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T129b Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T129b
- 825 825
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T102 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T102
- 826 826
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Tyr Boc-T102 Bts-Cpg Boc- (D) NMeAla Boc- (D) Tyr Boc-T102
- 828 828
- Bts-Chg Boc-(D)NMeAla Boc-(D)Leu Boc-T102a Bts-chg Boc- (D) NMeAla Boc- (D) Leu Boc-T102a
- 829 829
- Bts-Chg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T102a Bts-chg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T102a
- 831 831
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Cha Boc-T102 Bts-Cpg Boc- (D) NMeAla Boc- (D) Cha Boc-T102
- 832 832
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Tyr(3F) Boc-T102 Bts-Cpg Boc- (D) NMeAla Boc- (D) Tyr (3F) Boc-T102
(continuación) (continuation)
- Compuesto Compound
- AA1 AA2 AA3 Conector AA1 AA2 AA3 Connector
- 833 833
- Bts-Cpg Boc-(D)NMeAla Boc-(D)tBuAla Boc-T102 Bts-Cpg Boc- (D) NMeAla Boc- (D) tBuAla Boc-T102
- 851 851
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe Boc-T33a
- 853 853
- Bts-Nva Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T33a Bts-nva Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T33a
- 854 854
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T75a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T75a
- 855 855
- Bts-Ile Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T33a Bts-Ile Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T33a
- 856 856
- Bts-Ile Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T75a Bts-Ile Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T75a
- 857 857
- Bts-Val Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T33a Bts-val Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T33a
- 858 858
- Bts-Nva Boc-(D)NMeAla Boc-(D)Phe Boc-T33a Bts-nva Boc- (D) NMeAla Boc- (D) Phe Boc-T33a
- 859 859
- Bts-Nva Boc-(D)NMeAla Boc-(D)Phe Boc-T33b Bts-nva Boc- (D) NMeAla Boc- (D) Phe Boc-T33b
- 860 860
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Me) Boc-T9 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Me) Boc-T9
- 862 862
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T33a
- 863 863
- Bts-Nva Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T33a Bts-nva Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T33a
- 864 864
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T69 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T69
- 865 865
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe Boc-T69 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe Boc-T69
- 866 866
- Bts-Nva Boc-(D)NMeAla Boc-(D)Tyr(OMe) Boc-T33a Bts-nva Boc- (D) NMeAla Boc- (D) Tyr (OMe) Boc-T33a
- 867 867
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Tyr(OMe) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Tyr (OMe) Boc-T33a
- 869 869
- Bts-Val Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T9 Bts-val Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T9
- 870 870
- Bts-Val Boc-(D)NMeAla Boc-(D)Phe Boc-T33b Bts-val Boc- (D) NMeAla Boc- (D) Phe Boc-T33b
- 871 871
- Bts-Val Boc-(D)NMeAla Boc-(D)Phe Boc-T33a Bts-val Boc- (D) NMeAla Boc- (D) Phe Boc-T33a
- 872 872
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(2-Cl) Boc-T9 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (2-Cl) Boc-T9
- 873 873
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(3-Cl) Boc-T9 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (3-Cl) Boc-T9
- 874 874
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe Boc-T100 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe Boc-T100
- 876 876
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe Boc-T75a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe Boc-T75a
- 877 877
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T75a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T75a
- 878 878
- Bts-Ile Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T33a Bts-Ile Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T33a
- 923 923
- Bts-Ile Boc-(D)NMeAla Boc-(D)Phe T133 mediante RCM Bts-Ile Boc- (D) NMeAla Boc- (D) Phe T133 via RCM
- 934 934
- Bts-Ile Ddz-(D)NMeSer(But) Boc-(D)Phe Boc-T9 Bts-Ile Ddz- (D) NMeSer (But) Boc- (D) Phe Boc-T9
- 935 935
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T109a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T109a
- 936 936
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T109a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T109a
- 937 937
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T110a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T110a
- 938 938
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T110a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T110a
- 939 939
- Bts-Ile Ddz-(D)NMeSer(But) Boc-(D)Phe Boc-T33a Bts-Ile Ddz- (D) NMeSer (But) Boc- (D) Phe Boc-T33a
- 944 944
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T110a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T110a
(continuación) (continuation)
- Compuesto Compound
- AA1 AA2 AA3 Conector AA1 AA2 AA3 Connector
- 945 945
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T110a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T110a
- 946 946
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T100 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T100
- 947 947
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T100 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T100
- 950 950
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T112a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T112a
- 951 951
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T112a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T112a
- 954 954
- Bts-Ile Boc-(D)NMe(β-F)Ala Boc-(D)Phe Boc-T9 Bts-Ile Boc- (D) NMe (β-F) Ala Boc- (D) Phe Boc-T9
- 965 965
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe Boc-T116a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe Boc-T116a
- 966 966
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-Cl) Boc-T116a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-Cl) Boc-T116a
- 968 968
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T33a
- 969 969
- Bts-Ile Boc-(D)NMeAla Boc-(D)Leu Boc-T33a Bts-Ile Boc- (D) NMeAla Boc- (D) Leu Boc-T33a
- 972 972
- Bts-Cpg Boc-(D)NMeAla Boc-(D)2Pal Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) 2Pal Boc-T33a
- 973 973
- Bts-Cpg Boc-(D)NMeAla Boc-(D)3Pal Boc-T109a Bts-Cpg Boc- (D) NMeAla Boc- (D) 3Pal Boc-T109a
- 974 974
- Bts-Ile Boc-(D)NMeAla Boc-(D)3Pal Boc-T109a Bts-Ile Boc- (D) NMeAla Boc- (D) 3Pal Boc-T109a
- 975 975
- Bts-Cpg Boc-(D)NMeAla Boc-(D)3Pal Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) 3Pal Boc-T33a
- 976 976
- Bts-Ile Boc-(D)NMeAla Boc-(D)3Pal Boc-T33a Bts-Ile Boc- (D) NMeAla Boc- (D) 3Pal Boc-T33a
- 977 977
- Bts-Cpg Boc-(D)NMeAla Boc-(D)4Pal Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) 4Pal Boc-T33a
- 978 978
- Bts-Ile Boc-(D)NMeAla Boc-(D)4Pal Boc-T33a Bts-Ile Boc- (D) NMeAla Boc- (D) 4Pal Boc-T33a
- 979 979
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T109a Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T109a
- 981 981
- Bts-Ile Boc-(D)NMeAla Boc-(D)Leu Boc-T109a Bts-Ile Boc- (D) NMeAla Boc- (D) Leu Boc-T109a
- 982 982
- Bts-Chg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T33a Bts-chg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T33a
- 986 986
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T11 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T11
- 987 987
- Bts-Ile Boc-(D)NMeAla Boc-(D)Leu Boc-T11 Bts-Ile Boc- (D) NMeAla Boc- (D) Leu Boc-T11
- 988 988
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T11 Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T11
- 989 989
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T33a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T33a
- 991 991
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T109a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T109a
- 992 992
- Bts-Ile Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T11 Bts-Ile Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T11
- 993 993
- Bts-Ile Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T33a Bts-Ile Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T33a
- 994 994
- Bts-Ile Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T109a Bts-Ile Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T109a
- 995 995
- Bts-Cpg Boc-(D)NMeAla Boc-(D)2-Thi Boc-T11 Bts-Cpg Boc- (D) NMeAla Boc- (D) 2-Thi Boc-T11
- 996 996
- Bts-Ile Boc-(D)NMeAla Boc-(D)2-Thi Boc-T11 Bts-Ile Boc- (D) NMeAla Boc- (D) 2-Thi Boc-T11
- 997 997
- Bts-Thr(OMe) Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T11 Bts-Thr (OMe) Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T11
- 998 998
- Bts-Thr(OMe) Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T33a Bts-Thr (OMe) Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T33a
- 999 999
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T103a Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T103a
(continuación) (continuation)
- Compuesto Compound
- AA1 AA2 AA3 Conector AA1 AA2 AA3 Connector
- 1000 1000
- Bts-Ile Boc-(D)NMeAla Boc-(D)Leu Boc-T103a Bts-Ile Boc- (D) NMeAla Boc- (D) Leu Boc-T103a
- 1003 1003
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T108 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T108
- 1005 1005
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T114a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T114a
- 1006 1006
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T115a Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T115a
- 1007 1007
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T115a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T115a
- 1008 1008
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Cpa Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Cpa Boc-T33a
- 1009 1009
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T100a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T100a
- 1010 1010
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T101a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T101a
- 1011 1011
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T101c Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T101c
- 1014 1014
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Tle Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Tle Boc-T33a
- 1015 1015
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T100b Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T100b
- 1016 1016
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T100b Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T100b
- 1017 1017
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T118a/c Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T118a / c
- 1018 1018
- Bts-Cpg Boc-(D)NMeAla Boc-(D)(β-RMe)Phe(4-F) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) (β-RMe) Phe (4-F) Boc-T33a
- 1019 1019
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T105 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T105
- 1020 1020
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T105 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T105
- 1021 1021
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T119 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T119
- 1022 1022
- Bts-Ile Boc-(D)NMeAla Boc-(D)Leu Boc-T119 Bts-Ile Boc- (D) NMeAla Boc- (D) Leu Boc-T119
- 1023 1023
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T103a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T103a
- 1024 1024
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T100b Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T100b
- 1025 1025
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T105 Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T105
- 1026 1026
- Bts-Ile Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T103a Bts-Ile Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T103a
- 1027 1027
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T103a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T103a
- 1028 1028
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe Boc-T103a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe Boc-T103a
- 1029 1029
- Bts-Ile Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T103a Bts-Ile Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T103a
- 1030 1030
- Bts-Ile Boc-(D)NMeAla Boc-(D)Phe Boc-T103a Bts-Ile Boc- (D) NMeAla Boc- (D) Phe Boc-T103a
- 1031 1031
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe Boc-T119 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe Boc-T119
- 1032 1032
- Bts-Thr(OMe) Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T103a Bts-Thr (OMe) Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T103a
- 1033 1033
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T114c Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T114c
- 1034 1034
- Bts-Cpg Boc-(D)NMeAla Boc-(β-SMe)(D)Phe(4F) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (β-SMe) (D) Phe (4F) Boc-T33a
- 1035 1035
- Bts-Cpg Boc-(D)NMeAla Boc-(β-diMe)(D)Phe(4F) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (β-diMe) (D) Phe (4F) Boc-T33a
- 1036 1036
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Asp Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Asp Boc-T33a
- 1038 1038
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-CF3) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-CF3) Boc-T33a
(continuación) (continuation)
- Compuesto Compound
- AA1 AA2 AA3 Conector AA1 AA2 AA3 Connector
- 1039 1039
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(2,4diCl) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (2,4diCl) Boc-T33a
- 1040 1040
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(3,4diF) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (3,4diF) Boc-T33a
- 1041 1041
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(3,4,5-triF) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (3,4,5-triF) Boc-T33a
- 1042 1042
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(pentaF) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (pentaF) Boc-T33a
- 1043 1043
- Bts-Cpg Boc-(D)NMeAla Boc-(D)(tBuAla) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) (tBuAla) Boc-T33a
- 1044 1044
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Tle Boc-T109a Bts-Cpg Boc- (D) NMeAla Boc- (D) Tle Boc-T109a
- 1045 1045
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Cha Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Cha Boc-T33a
- 1046 1046
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Chg Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Chg Boc-T33a
- 1047 1047
- Bts-Cpg Boc-(D)NMeAla Boc-(DL)(ciclopentil)Ala Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (DL) (cyclopentyl) Wing Boc-T33a
- 1048 1048
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Cpg Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Cpg Boc-T33a
- 1049 1049
- Bts-Cpg Boc-(D)NMeAla Boc-(DL)Tyr(3-F) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (DL) Tyr (3-F) Boc-T33a
- 1050 1050
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Thr(But) Ddz-T33a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Thr (But) Ddz-T33a
- 1052 1052
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4-F) Boc-T102 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4-F) Boc-T102
- 1053 1053
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Tyr(3,5diBr) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Tyr (3,5diBr) Boc-T33a
- 1058 1058
- Bts-Cpg Boc-(D)NMeAla Boc-(2R,3R)(b-OH)Leu Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (2R, 3R) (b-OH) Leu Boc-T33a
- 1061 1061
- Bts-Chg Boc-(D)NMeAla Boc-(D)Leu Boc-T103a Bts-chg Boc- (D) NMeAla Boc- (D) Leu Boc-T103a
- 1062 1062
- Bts-Chg Boc-(D)NMeAla Boc-(D)Tyr Boc-T103a Bts-chg Boc- (D) NMeAla Boc- (D) Tyr Boc-T103a
- 1065 1065
- Bts-Cpg Boc-(D)NMeAla Boc-(DL)Tyr(3-F,OAc) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (DL) Tyr (3-F, OAc) Boc-T33a
- 1066 1066
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Tyr(3,5diBr,OAc) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Tyr (3,5diBr, OAc) Boc-T33a
- 1068 1068
- Bts-Cpg Boc-(D)NMeAla Boc-(β-SMe)(D)Tyr Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (β-SMe) (D) Tyr Boc-T33a
- 1069 1069
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T122a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T122a
- 1071 1071
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4F) Boc-T123a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4F) Boc-T123a
- 1072 1072
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T124d Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T124d
- 1074 1074
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T131a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T131a
- 1075 1075
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T131a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T131a
- 1076 1076
- Bts-Cpg Boc-(D)NMeAla Boc-(β-SMe)(D)Tyr Boc-T131a Bts-Cpg Boc- (D) NMeAla Boc- (β-SMe) (D) Tyr Boc-T131a
- 1078 1078
- Bts-Cpg Boc-(D)NMeAla Boc-(DL)Tyr(3F) Boc-T11 Bts-Cpg Boc- (D) NMeAla Boc- (DL) Tyr (3F) Boc-T11
- 1079 1079
- Bts-Cpg Boc-(D)NMeAla Boc-(D)mTyr Boc-T103a Bts-Cpg Boc- (D) NMeAla Boc- (D) mTyr Boc-T103a
- 1080 1080
- Bts-Cpg Boc-(D)NMeAla Boc-(β-SMe)(D)Tyr Boc-T11 Bts-Cpg Boc- (D) NMeAla Boc- (β-SMe) (D) Tyr Boc-T11
- 1081 1081
- Bts-Cpg Boc-(D)NMeAla Boc-(β-RMe)(D)Tyr Boc-T103a Bts-Cpg Boc- (D) NMeAla Boc- (β-RMe) (D) Tyr Boc-T103a
- 1082 1082
- Bts-Cpg Boc-(D)NMeAla Boc-(β-SMe)(D)Tyr Boc-T103a Bts-Cpg Boc- (D) NMeAla Boc- (β-SMe) (D) Tyr Boc-T103a
- 1083 1083
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T125b Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T125b
- 1084 1084
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T125b Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T125b
(continuación) (continuation)
- Compuesto Compound
- AA1 AA2 AA3 Conector AA1 AA2 AA3 Connector
- 1085 1085
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T125a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T125a
- 1086 1086
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T125a Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T125a
- 1087 1087
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T126c Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T126c
- 1088 1088
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T126c Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T126c
- 1089 1089
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T126a Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T126a
- 1090 1090
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Asp(OMe) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Asp (OMe) Boc-T33a
- 1098 1098
- Bts-Cpg Boc-(D)NMeAla Boc-(β-SMe)(D)Tyr Boc-T126c Bts-Cpg Boc- (D) NMeAla Boc- (β-SMe) (D) Tyr Boc-T126c
- 1099 1099
- Bts-Chg Boc-(D)NMeAla Boc-(D)Leu Boc-T33a Bts-chg Boc- (D) NMeAla Boc- (D) Leu Boc-T33a
- 1100 1100
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4F) Boc-T85 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4F) Boc-T85
- 1101 1101
- Bts-Cpg Boc-(D)NMeAla Boc-(DL)oTyr Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (DL) oTyr Boc-T33a
- 1103 1103
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phg(40H) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Phg (40H) Boc-T33a
- 1104 1104
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Tyr(3F) Boc-T33a Bts-Cpg Boc- (D) NMeAla Boc- (D) Tyr (3F) Boc-T33a
- 1105 1105
- Bts-Chg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T100a Bts-chg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T100a
- 1106 1106
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T104 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T104
- 1107 1107
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T130c Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T130c
- 1108 1108
- Bts-Chg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T33a Bts-chg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T33a
- 1109 1109
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Phe(4F) Boc-T87 Bts-Cpg Boc- (D) NMeAla Boc- (D) Phe (4F) Boc-T87
- 1110 1110
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T87 Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T87
- 1111 1111
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T87 Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T87
- 1112 1112
- Bts-Chg Boc-(D)NMeAla Boc-(D)Leu Boc-T69 Bts-chg Boc- (D) NMeAla Boc- (D) Leu Boc-T69
- 1113 1113
- Bts-Chg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T69 Bts-chg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T69
- 1114 1114
- Bts-Cpg Boc-(D)NMeAla Boc-(DL)CiclopentilAla Boc-T102 Bts-Cpg Boc- (D) NMeAla Boc- (DL) CiclopentilAla Boc-T102
- 1115 1115
- Bts-Cpg Boc-(D)NMeAla Boc-(DL)oTyr Boc-T102 Bts-Cpg Boc- (D) NMeAla Boc- (DL) oTyr Boc-T102
- 1116 1116
- Bts-Cpg Boc-(D)NMeAla Boc-(D)Leu Boc-T132a Bts-Cpg Boc- (D) NMeAla Boc- (D) Leu Boc-T132a
- 1118 1118
- Bts-Cpg Ddz-(D)NMeAla Ddz-(D)Tyr(But) Ddz-T104 Bts-Cpg Ddz- (D) NMeAla Ddz- (D) Tyr (But) Ddz-T104
- 1119 1119
- Bts-Cpg Boc-(D)NMeAla Boc-(β-SMe)(D)Tyr Boc-T101c Bts-Cpg Boc- (D) NMeAla Boc- (β-SMe) (D) Tyr Boc-T101c
La siguiente tabla presenta datos analíticos para compuestos representativos de la presente invención. The following table presents analytical data for representative compounds of the present invention.
Datos analíticos para compuestos de la invención (Compuestos 801, 807 y 825) y compuestos no de la invención Analytical data for compounds of the invention (Compounds 801, 807 and 825) and compounds not of the invention
- Compuesto N.º Compound No.
- Fórmula molecular MW calc (g/moles) EM [(M+H)+] hallado Molecular formula MW calc (g / moles) MS [(M + H) +] found
- 801 801
- C31H48N4O4 540,7 541 C31H48N4O4 540.7 541
- 802 802
- C28H42N4O4 498,7 499 C28H42N4O4 498.7 499
(continuación) (continuation)
- Compuesto N.º Compound No.
- Fórmula molecular MW calc (g/moles) EM [(M+H)+] hallado Molecular formula MW calc (g / moles) MS [(M + H) +] found
- 803 803
- C31H40N4O5 548,7 549 C31H40N4O5 548.7 549
- 807 807
- C28H44N4O4 500,7 501 C28H44N4O4 500.7 501
- 808 808
- C31H42N4O5 550,7 551 C31H42N4O5 550.7 551
- 810 810
- C26H39N4O4F 490,6 491 C26H39N4O4F 490.6 491
- 813 813
- C26H39N4O4F 490,6 491 C26H39N4O4F 490.6 491
- 816 816
- C26H38N4O4F2 508,6 509 C26H38N4O4F2 508.6 509
- 818 818
- C29H36N4O5F2 558,6 559 C29H36N4O5F2 558.6 559
- 819 819
- C28H44N4O4 500,7 501 C28H44N4O4 500.7 501
- 820 820
- C31H42N4O5 550,7 551 C31H42N4O5 550.7 551
- 822 822
- C27H41N4O4F 504,6 505 C27H41N4O4F 504.6 505
- 825 825
- C27H48N4O4 492,7 493 C27H48N4O4 492.7 493
- 826 826
- C30H46N4O5 542,7 543 C30H46N4O5 542.7 543
- 828 828
- C30H54N4O4 534,8 535 C30H54N4O4 534.8 535
- 829 829
- C33H52N4O5 584,8 585 C33H52N4O5 584.8 585
- 831 831
- C30H52N4O4 532,8 533 C30H52N4O4 532.8 533
- 832 832
- C30H45N4O5F 560,7 561 C30H45N4O5F 560.7 561
- 833 833
- C28H50N4O4 506,7 507 C28H50N4O4 506.7 507
- 851 851
- C30H40N4O4 520,7 521 C30H40N4O4 520.7 521
- 853 853
- C30H41N4O4F 540,7 541 C30H41N4O4F 540.7 541
- 854 854
- C30H38N4O4F2 556,6 557 C30H38N4O4F2 556.6 557
- 855 855
- C31H43N4O4F 554,7 555 C31H43N4O4F 554.7 555
- 856 856
- C31H42N4O4F2 572,7 573 C31H42N4O4F2 572.7 573
- 857 857
- C30H41N4O4F 540,7 541 C30H41N4O4F 540.7 541
- 858 858
- C30H42N4O4 522,7 523 C30H42N4O4 522.7 523
- 859 859
- C30H42N4O4 522,7 523 C30H42N4O4 522.7 523
- 860 860
- C30H40N4O4 520,7 521 C30H40N4O4 520.7 521
- 862 862
- C30H39N4O4Cl 555,1 555 C30H39N4O4Cl 555.1 555
- 863 863
- C30H41N4O4Cl 557,1 557 C30H41N4O4Cl 557.1 557
- 864 864
- C29H36N4O4FCl 559,1 559 C29H36N4O4FCl 559.1 559
- 865 865
- C29H37N4O4F 524,6 525 C29H37N4O4F 524.6 525
- 866 866
- C31H44N4O5 552,7 553 C31H44N4O5 552.7 553
- 867 867
- C31H42N4O5 550,7 551 C31H42N4O5 550.7 551
(continuación) (continuation)
- Compuesto N.º Compound No.
- Fórmula molecular MW calc (g/moles) EM [(M+H)+] hallado Molecular formula MW calc (g / moles) MS [(M + H) +] found
- 869 869
- C29H39N4O4Cl 543,1 543 C29H39N4O4Cl 543.1 543
- 870 870
- C30H42N4O4 522,7 523 C30H42N4O4 522.7 523
- 871 871
- C30H42N4O4 522,7 523 C30H42N4O4 522.7 523
- 872 872
- C29H37N4O4Cl 541,1 541 C29H37N4O4Cl 541.1 541
- 873 873
- C29H37N4O4Cl 541,1 541 C29H37N4O4Cl 541.1 541
- 874 874
- C31H40N4O4 532,7 533 C31H40N4O4 532.7 533
- 876 876
- C30H39N4O4F 538,7 539 C30H39N4O4F 538.7 539
- 877 877
- C30H38N4O4FCl 573,1 573 C30H38N4O4FCl 573.1 573
- 878 878
- C31H43N4O4Cl 571,2 571 C31H43N4O4Cl 571.2 571
- 923 923
- C32H46N4O4 550,7 551 C32H46N4O4 550.7 551
- 934 934
- C30H42N4O5 538,7 539 C30H42N4O5 538.7 539
- 935 935
- C30H38N4O4F2 556,6 557 C30H38N4O4F2 556.6 557
- 936 936
- C30H38N4O4FCl 573,1 573 C30H38N4O4FCl 573.1 573
- 937 937
- C30H38N4O4F2 556,6 557 C30H38N4O4F2 556.6 557
- 938 938
- C30H38N4O4FCl 573,1 573 C30H38N4O4FCl 573.1 573
- 939 939
- C31H44N4O5 552,7 553 C31H44N4O5 552.7 553
- 944 944
- C30H38N4O4FCl 573,1 573 C30H38N4O4FCl 573.1 573
- 945 945
- C30H38N4O4Cl2 589,6 589 C30H38N4O4Cl2 589.6 589
- 946 946
- C31H39N4O4F 550,7 551 C31H39N4O4F 550.7 551
- 947 947
- C31H39N4O4Cl 567,1 567 C31H39N4O4Cl 567.1 567
- 950 950
- C30H37N4O4F3 574,6 575 C30H37N4O4F3 574.6 575
- 951 951
- C30H37N4O4F2Cl 591,1 591 C30H37N4O4F2Cl 591.1 591
- 954 954
- C30H41N4O4F 540,7 541 C30H41N4O4F 540.7 541
- 965 965
- C32H43N4O4F 566,7 567 C32H43N4O4F 566.7 567
- 966 966
- C32H42N4O4FCl 601,2 601 C32H42N4O4FCl 601.2 601
- 968 968
- C27H42N4O4 486,6 487 C27H42N4O4 486.6 487
- 969 969
- C28H46N4O4 502,7 503 C28H46N4O4 502.7 503
- 972 972
- C29H39N5O4 521,7 522 C29H39N5O4 521.7 522
- 973 973
- C29H38N5O4F 539,6 540 C29H38N5O4F 539.6 540
- 974 974
- C30H42N5O4F 555,7 556 C30H42N5O4F 555.7 556
- 975 975
- C29H39N5O4 521,7 522 C29H39N5O4 521.7 522
- 976 976
- C30H43N5O4 537,7 538 C30H43N5O4 537.7 538
(continuación) (continuation)
- Compuesto N.º Compound No.
- Fórmula molecular MW calc (g/moles) EM [(M+H)+] hallado Molecular formula MW calc (g / moles) MS [(M + H) +] found
- 977 977
- C29H39N5O4 521,7 522 C29H39N5O4 521.7 522
- 978 978
- C30H43N5O4 537,7 538 C30H43N5O4 537.7 538
- 979 979
- C27H41N4O4F 504,6 505 C27H41N4O4F 504.6 505
- 981 981
- C28H45N4O4F 520,7 521 C28H45N4O4F 520.7 521
- 982 982
- C33H45N4O4F 580,7 581 C33H45N4O4F 580.7 581
- 986 986
- C25H39N5O4 473,6 474 C25H39N5O4 473.6 474
- 987 987
- C26H43N5O4 489,7 490 C26H43N5O4 489.7 490
- 988 988
- C28H37N5O5 523,6 524 C28H37N5O5 523.6 524
- 989 989
- C30H40N4O5 536,7 537 C30H40N4O5 536.7 537
- 991 991
- C30H39N4O5F 554,7 555 C30H39N4O5F 554.7 555
- 992 992
- C29H41N5O5 539,7 540 C29H41N5O5 539.7 540
- 993 993
- C31H44N4O5 552,7 553 C31H44N4O5 552.7 553
- 994 994
- C31H43N4O5F 570,7 571 C31H43N4O5F 570.7 571
- 995 995
- C26H35N5O4S 513,7 514 C26H35N5O4S 513.7 514
- 996 996
- C27H39N5O4S 529,7 530 C27H39N5O4S 529.7 530
- 997 997
- C30H41N4O5F 556,7 557 C30H41N4O5F 556.7 557
- 998 998
- C28H38N5O5F 543,6 544 C28H38N5O5F 543.6 544
- 999 999
- C26H41N5O4 487,6 488 C26H41N5O4 487.6 488
- 1000 1000
- C27H45N5O4 503,7 504 C27H45N5O4 503.7 504
- 1003 1003
- C31H41N4O4F 552,7 553 C31H41N4O4F 552.7 553
- 1005 1005
- C31H41N4O4F 552,7 553 C31H41N4O4F 552.7 553
- 1006 1006
- C27H41N4O4Cl 521,1 521 C27H41N4O4Cl 521.1 521
- 1007 1007
- C30H38N4O4FCl 573,1 573 C30H38N4O4FCl 573.1 573
- 1008 1008
- C27H39N4O4F 502,6 503 C27H39N4O4F 502.6 503
- 1009 1009
- C31H39N4O4F 550,7 551 C31H39N4O4F 550.7 551
- 1010 1010
- C31H41N4O4F 552,7 553 C31H41N4O4F 552.7 553
- 1011 1011
- C31H41N4O4F 552,7 553 C31H41N4O4F 552.7 553
- 1014 1014
- C27H42N4O4 486,6 487 C27H42N4O4 486.6 487
- 1015 1015
- C28H42N4O4 498,7 499 C28H42N4O4 498.7 499
- 1016 1016
- C31H39N4O4F 550,7 551 C31H39N4O4F 550.7 551
- 1017 1017
- C31H41N4O4F 552,7 553 C31H41N4O4F 552.7 553
- 1018 1018
- C31H41N4O4F 552,7 553 C31H41N4O4F 552.7 553
- 1019 1019
- C27H40N4O4 484,6 485 C27H40N4O4 484.6 485
(continuación) (continuation)
- Compuesto N.º Compound No.
- Fórmula molecular MW calc (g/moles) EM [(M+H)+] hallado Molecular formula MW calc (g / moles) MS [(M + H) +] found
- 1020 1020
- C30H37N4O4F 536,6 537 C30H37N4O4F 536.6 537
- 1021 1021
- C25H39N5O4 473,6 474 C25H39N5O4 473.6 474
- 1022 1022
- C26H43N5O4 489,7 490 C26H43N5O4 489.7 490
- 1023 1023
- C29H39N5O5 537,7 538 C29H39N5O5 537.7 538
- 1024 1024
- C31H40N4O5 548,7 549 C31H40N4O5 548.7 549
- 1025 1025
- C30H38N4O5 534,6 535 C30H38N4O5 534.6 535
- 1026 1026
- C30H43N5O5 553,7 554 C30H43N5O5 553.7 554
- 1027 1027
- C29H38N5O4F 539,6 540 C29H38N5O4F 539.6 540
- 1028 1028
- C29H39N5O4 521,7 522 C29H39N5O4 521.7 522
- 1029 1029
- C30H42N5O4F 555,7 556 C30H42N5O4F 555.7 556
- 1030 1030
- C30H43N5O4 537,7 538 C30H43N5O4 537.7 538
- 1031 1031
- C28H37N5O4 507,6 508 C28H37N5O4 507.6 508
- 1032 1032
- C29H40N5O5F 557,7 558 C29H40N5O5F 557.7 558
- 1033 1033
- C31H41N4O4F 552,7 553 C31H41N4O4F 552.7 553
- 1034 1034
- C31H41N4O4F 552,7 553 C31H41N4O4F 552.7 553
- 1035 1035
- C32H43N4O4F 566,7 567 C32H43N4O4F 566.7 567
- 1036 1036
- C25H36N4O6 488,6 489 C25H36N4O6 488.6 489
- 1038 1038
- C31H39N4O4F3 588,7 589 C31H39N4O4F3 588.7 589
- 1039 1039
- C30H38N4O4Cl2 589,6 589 C30H38N4O4Cl2 589.6 589
- 1040 1040
- C30H38N4O4F2 556,6 557 C30H38N4O4F2 556.6 557
- 1041 1041
- C30H37N4O4F3 574,6 575 C30H37N4O4F3 574.6 575
- 1042 1042
- C30H35N4O4F5 610,6 611 C30H35N4O4F5 610.6 611
- 1043 1043
- C28H44N4O4 500,7 501 C28H44N4O4 500.7 501
- 1044 1044
- C27H41N4O4F 504,6 505 C27H41N4O4F 504.6 505
- 1045 1045
- C30H46N4O4 526,7 527 C30H46N4O4 526.7 527
- 1046 1046
- C29H44N4O4 512,7 513 C29H44N4O4 512.7 513
- 1047 1047
- C29H44N4O4 512,7 513 C29H44N4O4 512.7 513
- 1048 1048
- C26H38N4O4 470,6 471 C26H38N4O4 470.6 471
- 1049 1049
- C30H39N4O5F 554,7 555 C30H39N4O5F 554.7 555
- 1050 1050
- C25H38N4O5 474,6 475 C25H38N4O5 474.6 475
- 1052 1052
- C30H45N4O4F 544,7 545 C30H45N4O4F 544.7 545
- 1053 1053
- C30H38N4O5Br2 694,5 695* C30H38N4O5Br2 694.5 695 *
- 1058 1058
- C27H42N4O5 502,6 503 C27H42N4O5 502.6 503
(continuación) (continuation)
- Compuesto N.º Compound No.
- Fórmula molecular MW calc (g/moles) EM [(M+H)+] hallado Molecular formula MW calc (g / moles) MS [(M + H) +] found
- 1061 1061
- C29H47N5O4 529,7 530 C29H47N5O4 529.7 530
- 1062 1062
- C32H45N5O5 579,7 580 C32H45N5O5 579.7 580
- 1065 1065
- C32H41N4O6F 596,7 597 C32H41N4O6F 596.7 597
- 1066 1066
- C32H40N4O6Br2 736,5 737* C32H40N4O6Br2 736.5 737 *
- 1068 1068
- C31H42N4O5 550,7 551 C31H42N4O5 550.7 551
- 1069 1069
- C31H42N4O5 550,7 551 C31H42N4O5 550.7 551
- 1071 1071
- C32H43N4O4F 566,7 567 C32H43N4O4F 566.7 567
- 1072 1072
- C31H42N4O5 550,7 551 C31H42N4O5 550.7 551
- 1074 1074
- C30H39N5O5 549,7 550 C30H39N5O5 549.7 550
- 1075 1075
- C27H41N5O4 499,6 500 C27H41N5O4 499.6 500
- 1076 1076
- C31H41N5O5 563,7 564 C31H41N5O5 563.7 564
- 1078 1078
- C28H36N5O5F 541,6 542 C28H36N5O5F 541.6 542
- 1079 1079
- C29H39N5O5 537,7 538 C29H39N5O5 537.7 538
- 1080 1080
- C29H39N5O5 537,7 538 C29H39N5O5 537.7 538
- 1081 1081
- C30H41N5O5 551,7 552 C30H41N5O5 551.7 552
- 1082 1082
- C30H41N5O5 551,7 552 C30H41N5O5 551.7 552
- 1083 1083
- C30H40N4O5 536,7 537 C30H40N4O5 536.7 537
- 1084 1084
- C27H42N4O4 486,6 487 C27H42N4O4 486.6 487
- 1085 1085
- C30H40N4O5 536,7 537 C30H40N4O5 536.7 537
- 1086 1086
- C27H42N4O4 486,6 487 C27H42N4O4 486.6 487
- 1087 1087
- C30H41N5O5 551,7 552 C30H41N5O5 551.7 552
- 1088 1088
- C27H43N5O4 501,7 502 C27H43N5O4 501.7 502
- 1089 1089
- C30H41N5O5 551,7 552 C30H41N5O5 551.7 552
- 1090 1090
- C26H38N4O6 502,6 503 C26H38N4O6 502.6 503
- 1098 1098
- C31H43N5O5 565,7 566 C31H43N5O5 565.7 566
- 1099 1099
- C30H48N4O4 528,7 529 C30H48N4O4 528.7 529
- 1100 1100
- C29H35N4O4F3 560,6 561 C29H35N4O4F3 560.6 561
- 1101 1101
- C30H40N4O5 536,7 537 C30H40N4O5 536.7 537
- 1103 1103
- C29H38N4O5 522,6 523 C29H38N4O5 522.6 523
- 1104 1104
- C30H39N4O5F 554,7 555 C30H39N4O5F 554.7 555
- 1105 1105
- C34H46N4O5 590,8 591 C34H46N4O5 590.8 591
- 1106 1106
- C26H46N4O4 478,7 479 C26H46N4O4 478.7 479
- 1107 1107
- C28H50N4O4 506,7 507 C28H50N4O4 506.7 507
(continuación) (continuation)
- Compuesto N.º Compound No.
- Fórmula molecular MW calc (g/moles) EM [(M+H)+] hallado Molecular formula MW calc (g / moles) MS [(M + H) +] found
- 1108 1108
- C33H46N4O5 578,7 579 C33H46N4O5 578.7 579
- 1109 1109
- C29H36N4O4F2 542,6 543 C29H36N4O4F2 542.6 543
- 1110 1110
- C29H37N4O5F 540,6 541 C29H37N4O5F 540.6 541
- 1111 1111
- C26H39N4O4F 490,6 491 C26H39N4O4F 490.6 491
- 1112 1112
- C29H45N4O4F 532,7 533 C29H45N4O4F 532.7 533
- 1113 1113
- C32H43N4O5F 582,7 583 C32H43N4O5F 582.7 583
- 1114 1114
- C29H50N4O4 518,7 519 C29H50N4O4 518.7 519
- 1115 1115
- C30H46N4O5 542,7 543 C30H46N4O5 542.7 543
- 1116 1116
- C28H48N4O4 504,7 505 C28H48N4O4 504.7 505
- 1117 1117
- C30H39N6O4F 566,7 567 C30H39N6O4F 566.7 567
- 1118 1118
- C29H44N4O5 528,7 529 C29H44N4O5 528.7 529
- 1119 1119
- C32H44N4O5 564,7 565 C32H44N4O5 564.7 565
- Notas * [(M+2+H)+] 1. Las fórmulas moleculares y pesos moleculares se calculan automáticamente a partir de la estructura mediante el software ActivityBase (ID Business Solutions, Ltd., Guildford, Surrey, RU). 2. M+H obtenido a partir del análisis de CL-EM usando procedimientos convencionales. 3. Todos los análisis se realizaron en el material después de la purificación preparativa. Notes * [(M + 2 + H) +] 1. Molecular formulas and molecular weights are automatically calculated from the structure using ActivityBase software (ID Business Solutions, Ltd., Guildford, Surrey, UK). 2. M + H obtained from the LC-MS analysis using conventional procedures. 3. All analyzes were performed on the material after preparative purification.
3. Procedimientos biológicos 3. Biological procedures
Los compuestos de la presente invención se evaluaron para su capacidad para interaccionar en el receptor de la The compounds of the present invention were evaluated for their ability to interact in the receptor of the
5 grelina humana. Puede emplearse un ensayo de unión a radioligando competitiva, ensayo de fluorescencia o ensayo funcional de aequorina. Tales procedimientos pueden realizarse en un modo de alta resolución para permitir la evaluación simultánea de muchos compuestos. 5 human ghrelin A competitive radioligand binding assay, fluorescence assay or aequorin functional assay can be used. Such procedures can be performed in a high resolution mode to allow simultaneous evaluation of many compounds.
Se conocen procedimientos de ensayo específicos para los receptores de GHS humano (GHS-R1a), de cerdo y de rata (patente de EE.UU. N.º 6.242.199, solicitudes de patente internacional N.º WO 97/21730 y 97/22004), además Specific test procedures are known for human GHS (GHS-R1a), pig and rat (US Patent No. 6,242,199, International Patent Applications No. WO 97/21730 and 97 / 22004), in addition
10 del receptor de GHS canino (patente de EE.UU. N.º 6.645.726), y su uso en generalmente identificar agonistas y antagonistas de los mismos. 10 of the canine GHS receptor (US Patent No. 6,645,726), and its use in generally identifying agonists and antagonists thereof.
Procedimientos apropiados para determinar la actividad funcional e in vivo de los compuestos de la presente invención que interaccionan en el receptor de la grelina humana también se describen más adelante. Además, pueden usarse procedimientos establecidos en la materia para determinar otros parámetros importantes para su uso Appropriate procedures for determining the functional and in vivo activity of the compounds of the present invention that interact in the human ghrelin receptor are also described below. In addition, procedures established in the art can be used to determine other parameters important for use
15 como agentes farmacéuticos, tales como farmacocinética, permeabilidad de Caco-2, unión a proteínas del plasma. 15 as pharmaceutical agents, such as pharmacokinetics, Caco-2 permeability, plasma protein binding.
A. Ensayo de unión a radioligando competitivo (receptor de la grelina) A. Competitive radioligand binding assay (ghrelin receptor)
Puede llevarse a cabo un ensayo de unión competitiva en el receptor del secretagogo de la hormona de crecimiento humana (hGHS-R1a) análogamente a los ensayos descritos en la bibliografía (Bednarek, M.A.; et al. J. Med. Chem. 2000, 43, 4370-4376; Palucki, B.L.; et al. Bioorg. Med. Chem. Lett. 2002, 11, 1955-1957). Véanse también las A competitive binding assay can be performed on the human growth hormone secretagogue receptor (hGHS-R1a) analogously to the assays described in the literature (Bednarek, MA; et al. J. Med. Chem. 2000, 43 , 4370-4376; Palucki, BL; et al. Bioorg. Med. Chem. Lett. 2002, 11, 1955-1957). See also the
20 solicitudes de patente de EE.UU. N.º de serie 11/149.512 y 11/149.731. La actividad de unión en el receptor de la grelina para compuestos representativos de la presente invención se muestra en los ejemplos más adelante. 20 U.S. patent applications Serial No. 11 / 149,512 and 11 / 149,731. The binding activity at the ghrelin receptor for representative compounds of the present invention is shown in the examples below.
B. Ensayo funcional de aequorina (receptor de la grelina) B. Functional test of aequorin (ghrelin receptor)
La actividad funcional de los compuestos de la invención que se encontró que se unían al receptor de GHS-R1a puede determinarse usando los procedimientos descritos en la bibliografía, que también pueden usarse como The functional activity of the compounds of the invention that were found to bind to the GHS-R1a receptor can be determined using the procedures described in the literature, which can also be used as
25 cribado primario para la actividad del receptor de la grelina en un modo de alto rendimiento. Véanse también las solicitudes de patente de EE.UU. N.º de serie 11/149.512 y 11/149731 (LePoul, E.; et al. J. Biomol. Screen. 2002, 7, 57-65; Bednarek, M.A.; et al. J. Med. Chem. 2000, 43, 4370-4376; Palucki, B.L.; et al. Bioorg. Med. Chem. Lett. 2001, 11, 1955-1957). La actividad funcional en el receptor de la grelina para compuestos representativos de la presente invención se presenta en los ejemplos. Primary screening for ghrelin receptor activity in a high performance mode. See also US patent applications. Serial No. 11 / 149,512 and 11/149731 (LePoul, E .; et al. J. Biomol. Screen. 2002, 7, 57-65; Bednarek, MA; et al. J. Med. Chem. 2000, 43, 4370-4376; Palucki, BL; et al. Bioorg. Med. Chem. Lett. 2001, 11, 1955-1957). Functional activity in the ghrelin receptor for representative compounds of the present invention is presented in the examples.
de Ogilvie), síndrome del intestino corto, vómitos, síndrome del intestino irritable (EII) predominante en estreñimiento, estreñimiento crónico, síndrome de dispepsia asociada al cáncer, vaciamiento gástrico retardado, disfunción gastrointestinal o vaciamiento gástrico retardado en pacientes con enfermedad de Parkinson, disfunción gastrointestinal o vaciamiento gástrico retardado en distrofia muscular miotónica, disfunción gastrointestinal o of Ogilvie), short bowel syndrome, vomiting, irritable bowel syndrome (IBD) predominantly in constipation, chronic constipation, cancer-associated dyspepsia syndrome, delayed gastric emptying, gastrointestinal dysfunction or delayed gastric emptying in patients with Parkinson's disease, dysfunction gastrointestinal or delayed gastric emptying in myotonic muscular dystrophy, gastrointestinal dysfunction or
5 vaciamiento gástrico retardado en pacientes con escleroderma, enfermedad por reflujo gastroesofágico (GERD), úlceras gástricas o enfermedad de Crohn. 5 Delayed gastric emptying in patients with scleroderma, gastroesophageal reflux disease (GERD), gastric ulcers or Crohn's disease.
También en el presente documento se describen procedimientos de tratamiento de un caballo o canino para un trastorno gastrointestinal que comprende administrar una cantidad terapéuticamente eficaz de un compuesto de la invención. El trastorno gastrointestinal puede ser íleo o cólico. Also described herein are methods of treating a horse or canine for a gastrointestinal disorder comprising administering a therapeutically effective amount of a compound of the invention. The gastrointestinal disorder can be ileus or colic.
10 Como se usa en el presente documento, "tratamiento" no significa necesariamente la implicación de cura o abolición completa del trastorno o síntomas asociados al mismo. 10 As used herein, "treatment" does not necessarily mean the implication of complete cure or abolition of the disorder or symptoms associated therewith.
Los compuestos de la presente invención pueden utilizarse adicionalmente para la preparación de un medicamento para el tratamiento de una variedad de afecciones médicas que incluyen, pero no se limitan a, trastornos metabólicos y/o endocrinos, trastornos gastrointestinales, trastornos cardiovasculares, trastornos del sistema The compounds of the present invention can be further used for the preparation of a medicament for the treatment of a variety of medical conditions that include, but are not limited to, metabolic and / or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, system disorders
15 nervioso central, obesidad y trastornos asociados a la obesidad, trastornos genéticos, trastornos óseos, trastornos hiperproliferativos y trastornos inflamatorios. 15 central nervous, obesity and disorders associated with obesity, genetic disorders, bone disorders, hyperproliferative disorders and inflammatory disorders.
Realizaciones adicionales de la presente invención se describirán ahora con referencia a los siguientes ejemplos. Debe apreciarse que estos ejemplos son para los fines de ilustrar realizaciones de la presente invención, y no limitan el alcance de la invención. Additional embodiments of the present invention will now be described with reference to the following examples. It should be appreciated that these examples are for the purpose of illustrating embodiments of the present invention, and do not limit the scope of the invention.
20 Ejemplos 20 Examples
Ejemplo 1 Example 1
Actividad de unión Union activity
La siguiente tabla presenta la actividad de unión en el receptor de la grelina humana para compuestos de la invención (Compuestos 801, 807 y 825) y compuestos no de la invención. The following table presents the binding activity in the human ghrelin receptor for compounds of the invention (Compounds 801, 807 and 825) and non-invention compounds.
- Compuesto N.º Compound No.
- Ki (nM)a Compuesto N.º Ki (nM)a Ki (nM) a Compound No. Ki (nM) a
- 801 801
- A 1008 C TO 1008 C
- 802 802
- C 1009 A C 1009 TO
- 803 803
- C 1010 B C 1010 B
- 807 807
- B 1011 B B 1011 B
- 808 808
- C 1014 D C 1014 D
- 809 809
- C 1015 D C 1015 D
- 810 810
- C 1016 C C 1016 C
- 813 813
- B 1017a C B 1017a C
- 816 816
- B 1017b D B 1017b D
- 818 818
- B 1018 C B 1018 C
- 819 819
- B 1019a D B 1019a D
- 820 820
- C 1019b E C 1019b AND
- 822 822
- C 1020a C C 1020a C
- 825 825
- B 1020b C B 1020b C
- 826 826
- C 1021 E C 1021 AND
- 828 828
- A 1022 D TO 1022 D
- 829 829
- A 1023 C TO 1023 C
(continuación) (continuation)
- Compuesto N.º Compound No.
- Ki (nM)a Compuesto N.º Ki (nM)a Ki (nM) a Compound No. Ki (nM) a
- 831 831
- A 1024 C TO 1024 C
- 832 832
- A 1025 D TO 1025 D
- 833 833
- B 1026 C B 1026 C
- 851 851
- C 1027 C C 1027 C
- 853 853
- C 1028 C C 1028 C
- 854 854
- C 1029 B C 1029 B
- 855 855
- C 1030 C C 1030 C
- 856 856
- D 1031 C D 1031 C
- 857 857
- D 1032 D D 1032 D
- 858 858
- D 1033 C D 1033 C
- 859 859
- D 1034 C D 1034 C
- 860 860
- B 1035 C B 1035 C
- 862 862
- B 1036 E B 1036 AND
- 863 863
- C 1038 C C 1038 C
- 864 864
- B 1039 C B 1039 C
- 865 865
- C 1040 C C 1040 C
- 866 866
- C 1041 C C 1041 C
- 867 867
- C 1042 C C 1042 C
- 869 869
- C 1043 C C 1043 C
- 870 870
- D 1044 D D 1044 D
- 871 871
- D 1045 C D 1045 C
- 872 872
- B 1046 C B 1046 C
- 873 873
- C 1047 C C 1047 C
- 874 874
- C 1048 E C 1048 AND
- 876 876
- C 1049 C C 1049 C
- 877 877
- C 1050 E C 1050 AND
- 878 878
- C 1052 A C 1052 TO
- 923 923
- C 1053 C C 1053 C
- 934a 934a
- C 1058 C C 1058 C
- 934b 934b
- E 1061 C AND 1061 C
- 935 935
- C 1062 B C 1062 B
- 936 936
- C 1065 C C 1065 C
(continuación) (continuation)
- Compuesto N.º Compound No.
- Ki (nM)a Compuesto N.º Ki (nM)a Ki (nM) a Compound No. Ki (nM) a
- 937 937
- D 1066 C D 1066 C
- 938 938
- C 1068 C C 1068 C
- 939 939
- C 1069 C C 1069 C
- 944 944
- D 1071 D D 1071 D
- 945 945
- D 1072 D D 1072 D
- 946 946
- B 1074 C B 1074 C
- 947 947
- B 1075 C B 1075 C
- 950 950
- D 1076 C D 1076 C
- 951 951
- D 1078 C D 1078 C
- 954 954
- D 1079 C D 1079 C
- 965 965
- D 1080 C D 1080 C
- 966 966
- D 1081 E D 1081 AND
- 968 968
- C 1082 D C 1082 D
- 969a 969a
- C 1083 C C 1083 C
- 969b 969b
- C 1084 C C 1084 C
- 972 972
- C 1085a C C 1085a C
- 973a 973a
- C 1085b C C 1085b C
- 973b 973b
- E 1086 C AND 1086 C
- 974 974
- C 1087a D C 1087a D
- 975 975
- C 1087b C C 1087b C
- 976 976
- C 1088 D C 1088 D
- 977 977
- D 1089a C D 1089a C
- 978 978
- C 1089b D C 1089b D
- 979 979
- C 1090 D C 1090 D
- 981 981
- B 1098a D B 1098a D
- 982 982
- A 1098b C TO 1098b C
- 986 986
- E 1099 A AND 1099 TO
- 987 987
- D 1100 B D 1100 B
- 988 988
- C 1101 D C 1101 D
- 989 989
- C 1103 E C 1103 AND
- 991 991
- C 1104 C C 1104 C
- 992 992
- C 1105 A C 1105 TO
- 993 993
- C 1106 C C 1106 C
(continuación) (continuation)
- Compuesto N.º Compound No.
- Ki (nM)a Compuesto N.º Ki (nM)a Ki (nM) a Compound No. Ki (nM) a
- 994 994
- C 1107 C C 1107 C
- 995 995
- C 1108 A C 1108 TO
- 996a 996a
- B 1109 B B 1109 B
- 996b 996b
- D 1110 C D 1110 C
- 997 997
- D 1111 C D 1111 C
- 998 998
- C 1112 A C 1112 TO
- 999a 999a
- E 1113 A AND 1113 TO
- 999b 999b
- D 1114 A D 1114 TO
- 1000 1000
- D 1115 D D 1115 D
- 1003 1003
- C 1116 C C 1116 C
- 1005 1005
- C 1118 B C 1118 B
- 1006 1006
- D 1119 C D 1119 C
- 1007 1007
- C C
- a Actividad de unión determinada usando el procedimiento convencional A, los valores de Ki se expresan del siguiente modo: A ≤ 1 nM, B ≤ 10 nM, C ≤ 100 nM, D ≤ 500 nM, E > 500 nM. a Bonding activity determined using the conventional procedure A, Ki values are expressed as follows: A ≤ 1 nM, B ≤ 10 nM, C ≤ 100 nM, D ≤ 500 nM, E> 500 nM.
Ejemplo 2 Actividad funcional Example 2 Functional Activity
La siguiente tabla presente la actividad funcional en el receptor de la grelina humana para un compuesto de la invención (Compuesto 807) y compuestos no de la invención. The following table shows the functional activity in the human ghrelin receptor for a compound of the invention (Compound 807) and compounds not of the invention.
- Compuesto Compound
- CE50 (nM) EC50 (nM)
- 807 807
- A TO
- 877 877
- A TO
- 968 968
- C C
- 969a 969a
- C C
- 969b 969b
- C C
- 973a 973a
- C C
- 973b 973b
- C C
- 975 975
- D D
- 976 976
- C C
- 982 982
- A TO
- 802 802
- B B
- 1009 1009
- A TO
- 1018 1018
- C C
(continuación) (continuation)
- Compuesto Compound
- CE50 (nM) EC50 (nM)
- 1033 1033
- B B
- 1043 1043
- B B
- 1058 1058
- B B
- 1061 1061
- B B
- 1062 1062
- A TO
- b Actividad funcional determinada usando el procedimiento convencional B, los valores de CE50 se expresan del siguiente modo: A ≤ 50 nM, B ≤100 nM, C ≤ 400 nM, D > 400 nM b Functional activity determined using conventional procedure B, EC50 values are expressed as follows: A ≤ 50 nM, B ≤100 nM, C ≤ 400 nM, D> 400 nM
Ejemplo 3 Example 3
Farmacocinética oral Oral pharmacokinetics
5 La siguiente tabla presenta los datos de biodisponibilidad oral y de semivida de eliminación en la rata para compuestos de la presente invención (Compuestos 801, 807 y 825) y compuestos no de la invención. Los parámetros se determinaron por HPLC-EM después de la administración por vía oral de una dosis de 8 mg/kg de compuesto, excepto para el compuesto 822 donde se usó una dosis de 2 mg/kg. The following table presents the oral bioavailability and elimination half-life data in the rat for compounds of the present invention (Compounds 801, 807 and 825) and non-invention compounds. The parameters were determined by HPLC-MS after oral administration of a dose of 8 mg / kg of compound, except for compound 822 where a dose of 2 mg / kg was used.
- Compuesto Compound
- Semivida de eliminación (t1/2, rata, min) Biodisponibilidad oral (rata, % de F) Elimination half-life (t1 / 2, rat, min) Oral bioavailability (rat,% F)
- 801 801
- 42 4 42 4
- 802 802
- 160 26 160 26
- 803 803
- 151 9 151 9
- 807 807
- 197 23 197 2. 3
- 808 808
- 238 18 238 18
- 810 810
- 116 15 116 fifteen
- 813 813
- 31 4 31 4
- 819 819
- 116 12 116 12
- 820 820
- 137 18 137 18
- 822 822
- 65 51 65 51
- 825 825
- 101 37 101 37
- 826 826
- 77 29 77 29
- 829 829
- 45 8 Four. Five 8
- 831 831
- 120 15 120 fifteen
- 854 854
- 223 22 223 22
- 862 862
- 77 22 77 22
- 877 877
- 255 15 255 fifteen
- 935 935
- 42 11 42 eleven
- 968 968
- 103 26 103 26
(continuación) (continuation)
- Compuesto Compound
- Pap A a B cm/s x10-6 Pap B a A cm/s x10-6 B a A/A a B Pap A at B cm / s x10-6 Pap B at W cm / s x10-6 B to A / A to B
- 811 811
- 125 198 1,59 125 198 1.59
- 825 825
- 113 123 1,08 113 123 1.08
- 826 826
- 11,2 46,9 4,18 11.2 46.9 4.18
Ejemplo 6 Unión a proteínas Example 6 Protein binding
La siguiente tabla presenta los datos de unión a proteínas para compuestos de la presente invención (Compuestos 801, 807 y 825) y compuestos no de la invención en tanto plasma humano como de rata. The following table presents the protein binding data for compounds of the present invention (Compounds 801, 807 and 825) and non-invention compounds in both human and rat plasma.
- Compuesto Compound
- Concentración de prueba (µg/ml) Unión a proteínas de plasma humano (%) Unión a proteínas de plasma de rata (%) Test concentration (µg / ml) Binding to human plasma proteins (%) Rat plasma protein binding (%)
- 801 801
- 3 88,4 nd 3 88.4 nd
- 802 802
- 1 93,4 99,8 one 93.4 99.8
- 803 803
- 1 97,8 99,1 one 97.8 99.1
- 807 807
- 5 99,3 84,0 5 99.3 84.0
- 808 808
- 5 99,9 89,2 5 99.9 89.2
- 809 809
- 3 88,4 92,8 3 88.4 92.8
- 810 810
- 3 78,9 nd 3 78.9 nd
- 819 819
- 3 95,2 98,2 3 95.2 98.2
- 820 820
- 3 99,0 98,8 3 99.0 98.8
- 822 822
- 3 93,0 99,1 3 93.0 99.1
- 825 825
- 1 83 96,6 one 83 96.6
- 825 825
- 5 70 73 5 70 73
- 826 826
- 3 94,3 97,2 3 94.3 97.2
- 828 828
- 3 76,8 nd 3 76.8 nd
- 829 829
- 3 91,6 nd 3 91.6 nd
- 832 832
- 3 88,9 97,3 3 88.9 97.3
- 833 833
- 3 77,4 94,0 3 77.4 94.0
- 1118 1118
- 3 92,8 95,5 3 92.8 95.5
- nd = no determinado nd = not determined
Ejemplo 7 Example 7
Modelo de vaciamiento gástrico Gastric emptying model
10 Los efectos de los compuestos de la invención (Compuestos 801 y 807) y compuestos no de la invención en el modelo de vaciamiento gástrico de rata descrito en el procedimiento convencional E se proporcionan en la siguiente tabla. En los casos en los que un experimento se realizó múltiples veces, se presenta el promedio de los resultados individuales. The effects of the compounds of the invention (Compounds 801 and 807) and compounds not of the invention in the rat gastric emptying model described in conventional procedure E are provided in the following table. In cases where an experiment was performed multiple times, the average of the individual results is presented.
Aumento del porcentaje en el vaciamiento gástrico después de la administración por vía oral Increase in the percentage of gastric emptying after oral administration
- Compuesto Compound
- Dosis (mg/kg) Dose (mg / kg)
- 1 one
- 3 10 30 3 10 30
- 801 801
- - 27 31 40 - 27 31 40
- 802 802
- 12 11 26 - 12 eleven 26 -
- 807 807
- 17 31 41 - 17 31 41 -
- 808 808
- 18 37 40 - 18 37 40 -
- 809 809
- - 5 - - - 5 - -
- 813 813
- - 11 - - - eleven - -
- 818 818
- - 11 - - - eleven - -
- 819 819
- 9 21 18 - 9 twenty-one 18 -
- 820 820
- 6 20 22 - 6 twenty 22 -
- 822 822
- - 6 - - - 6 - -
- 826 826
- 19 12 30 - 19 12 30 -
- 828 828
- - 24 - - - 24 - -
- 829 829
- - 28 - - - 28 - -
- 831 831
- - 32 - - - 32 - -
- 832 832
- - 13 - - - 13 - -
- 833 833
- - 6 - - - 6 - -
- metoclopramida metoclopramide
- - - - 35 - - - 35
- -indica no determinado -indicated not determined
Con las semividas relativamente largas presentadas por algunos de estos compuestos como se muestra en el Ejemplo 3, podría esperarse que sus efectos sobre el vaciamiento gástrico pudieran prolongarse. De hecho, esto se 5 confirmó para el compuesto 807, donde las tasas de vaciamiento gástrico siguieron elevadas (18-23 %) hasta 24 h después de la dosis. With the relatively long half-lives presented by some of these compounds as shown in Example 3, it could be expected that their effects on gastric emptying could be prolonged. In fact, this was confirmed for compound 807, where gastric emptying rates remained high (18-23%) until 24 h after the dose.
También es de mención la eficacia del compuesto 801 en la promoción del vaciamiento gástrico aún cuando su biodisponibilidad oral fuera solo del 4 % (Ejemplo 3). Esto sugiere que el compuesto y ciertos otros de la invención poseen actividad pro-motilidad localmente en el sistema GI, mientras que limitan la exposición sistémica. Una Also noteworthy is the efficacy of compound 801 in promoting gastric emptying even if its oral bioavailability was only 4% (Example 3). This suggests that the compound and certain others of the invention possess pro-motility activity locally in the GI system, while limiting systemic exposure. A
10 característica tal podría conducir a efectos secundarios reducidos en su uso como agente farmacéutico. Such characteristic could lead to reduced side effects in its use as a pharmaceutical agent.
Ejemplo 8 Example 8
Íleo postoperatorio Postoperative ileus
Efecto del compuesto representativo en el tratamiento de íleo postoperatorio en rata. Effect of the representative compound in the treatment of postoperative ileus in rat.
Procedimientos Procedures
15 1. Modelo adaptado de Kälff et al. (1998), Ann Surg 228:652-63. 15 1. Model adapted from Kälff et al. (1998), Ann Surg 228: 652-63.
- 2. 2.
- Ratas (macho, Sprague-Dawley, 250-300 g) se implantan con catéteres de la vena yugular para acomodar la dosificación de artículos de prueba. Rats (male, Sprague-Dawley, 250-300 g) are implanted with jugular vein catheters to accommodate the dosing of test items.
- 3. 3.
- Las ratas ayunan durante la noche, se anestesian con isoflurano y se someten a cirugía abdominal. Rats fast overnight, are anesthetized with isoflurane and undergo abdominal surgery.
4. Tras una incisión abdominal, se evisceran el intestino delgado, el ciego y el intestino grueso durante un 20 periodo de 15 min y se mantienen húmedos con solución salina. 4. After an abdominal incision, the small intestine, the cecum and the large intestine are eviscerated for a period of 15 minutes and kept moist with saline solution.
5. Se realiza un "recorrido del intestino", una manipulación clínicamente relevante de los intestinos caracterizada por pellizcar primero el intestino delgado superior y continuar esta manipulación hacia abajo a través del intestino 5. A "bowel path" is performed, a clinically relevant manipulation of the intestines characterized by first pinching the upper small intestine and continuing this manipulation down through the intestine
Los rendimientos globales para el compuesto 825 de la invención y otros compuestos preparados usando el enfoque general descrito para 801 y 807 se presentan en la siguiente tabla. The overall yields for compound 825 of the invention and other compounds prepared using the general approach described for 801 and 807 are presented in the following table.
Rendimientos de macrociclos representativos adicionales Additional representative macrocycle yields
- Compuesto Compound
- Rendimiento global Overall performance
- 808 808
- 38,2 % 38.2%
- 809 809
- 36,3 % 36.3%
- 810 810
- 42,5 % 42.5%
- 820 820
- 5,6 % 5.6%
- 825 825
- 56,5 % 56.5%
- 826 826
- 27,5 % 27.5%
- 1003 1003
- 7,8 % 7.8%
- 1005 1005
- 15,1 % 15.1%
- 1006 1006
- 4,2 % 4.2%
- 1007 1007
- 5,6 % 5.6%
- 1010 1010
- 43,5 % 43.5%
- 1011 1011
- 52,6 % 52.6%
- 1017 1017
- 35,3 % 35.3%
- 1018 1018
- 38,5 % 38.5%
- 1033 1033
- 25,0 % 25.0%
- 1034 1034
- 9,6 % 9.6%
- 1055 1055
- 19,9 % 19.9%
- 1069 1069
- 9,9 % 9.9%
- 1072 1072
- 10,5 % 10.5%
- 1084 1084
- 28,9 % 28.9%
- 1087 1087
- 38,1 % 38.1%
- 1088 1088
- 17,2 % 17.2%
- 1089 1089
- 24,4 % 24.4%
- 1098 1098
- 20,3 % 20.3%
- 1106 1106
- 49,1 % 49.1%
- 1107 1107
- 65,5 % 65.5%
- 1118 1118
- 33,0 % 33.0%
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| US889163P | 2007-02-09 | ||
| PCT/US2008/001754 WO2008130464A1 (en) | 2007-02-09 | 2008-02-08 | Macrocyclic ghrelin receptor modulators and methods of using the same |
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| US7476653B2 (en) * | 2003-06-18 | 2009-01-13 | Tranzyme Pharma, Inc. | Macrocyclic modulators of the ghrelin receptor |
| US8921521B2 (en) | 2003-06-18 | 2014-12-30 | Ocera Therapeutics, Inc. | Macrocyclic modulators of the Ghrelin receptor |
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2008
- 2008-02-08 JP JP2009549129A patent/JP2010518090A/en active Pending
- 2008-02-08 KR KR1020097018709A patent/KR20090107088A/en not_active Application Discontinuation
- 2008-02-08 EP EP08799889.4A patent/EP2118080B1/en active Active
- 2008-02-08 MX MX2009008574A patent/MX2009008574A/en not_active Application Discontinuation
- 2008-02-08 ES ES12195556.1T patent/ES2602789T3/en active Active
- 2008-02-08 ES ES08799889.4T patent/ES2604943T3/en active Active
- 2008-02-08 AU AU2008241532A patent/AU2008241532A1/en not_active Abandoned
- 2008-02-08 BR BRPI0807046-6A patent/BRPI0807046A2/en not_active IP Right Cessation
- 2008-02-08 CA CA2677399A patent/CA2677399C/en not_active Expired - Fee Related
- 2008-02-08 EP EP12195556.1A patent/EP2644618B1/en not_active Not-in-force
- 2008-02-08 WO PCT/US2008/001754 patent/WO2008130464A1/en active Application Filing
- 2008-02-08 EA EA200901077A patent/EA200901077A1/en unknown
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2016
- 2016-06-09 US US15/178,303 patent/US9949949B2/en active Active
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Also Published As
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|---|---|
| US20080194672A1 (en) | 2008-08-14 |
| US20170042858A1 (en) | 2017-02-16 |
| KR20090107088A (en) | 2009-10-12 |
| JP2014141507A (en) | 2014-08-07 |
| AU2008241532A1 (en) | 2008-10-30 |
| BRPI0807046A2 (en) | 2015-05-26 |
| JP6047514B2 (en) | 2016-12-21 |
| CN101657436A (en) | 2010-02-24 |
| EA200901077A1 (en) | 2010-04-30 |
| US9949949B2 (en) | 2018-04-24 |
| EP2644618A1 (en) | 2013-10-02 |
| US10258602B2 (en) | 2019-04-16 |
| US9371297B2 (en) | 2016-06-21 |
| EP2118080A1 (en) | 2009-11-18 |
| ES2602789T3 (en) | 2017-02-22 |
| US20180228768A1 (en) | 2018-08-16 |
| JP2010518090A (en) | 2010-05-27 |
| MX2009008574A (en) | 2009-12-09 |
| CA2677399A1 (en) | 2008-10-30 |
| CA2677399C (en) | 2016-09-13 |
| EP2644618B1 (en) | 2016-08-17 |
| EP2118080B1 (en) | 2016-08-31 |
| WO2008130464A1 (en) | 2008-10-30 |
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